An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy
Identifieur interne : 000037 ( Pmc/Corpus ); précédent : 000036; suivant : 000038An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy
Auteurs : Thanigaimalai Pillaiyar ; Manoj Manickam ; Vigneshwaran Namasivayam ; Yoshio Hayashi ; Sang-Hun JungSource :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2016.
Abstract
Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10–15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CLpro, has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CLpro chemotherapies discovered during the last 12 years (2003–2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CLpro. Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.
Url:
DOI: 10.1021/acs.jmedchem.5b01461
PubMed: 26878082
PubMed Central: 7075650
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">An Overview of
Severe Acute Respiratory Syndrome–Coronavirus
(SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule
Chemotherapy</title><author><name sortKey="Pillaiyar, Thanigaimalai" sort="Pillaiyar, Thanigaimalai" uniqKey="Pillaiyar T" first="Thanigaimalai" last="Pillaiyar">Thanigaimalai Pillaiyar</name><affiliation><nlm:aff id="aff1">Pharmaceutical Institute, Pharmaceutical Chemistry I,<institution>University of Bonn</institution>, An der Immenburg 4, D-53121 Bonn,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Manickam, Manoj" sort="Manickam, Manoj" uniqKey="Manickam M" first="Manoj" last="Manickam">Manoj Manickam</name><affiliation><nlm:aff id="aff3">College of Pharmacy and Institute of Drug Research and Development,<institution>Chungnam National University</institution>, Daejeon 34134,<country>South Korea</country></nlm:aff></affiliation></author><author><name sortKey="Namasivayam, Vigneshwaran" sort="Namasivayam, Vigneshwaran" uniqKey="Namasivayam V" first="Vigneshwaran" last="Namasivayam">Vigneshwaran Namasivayam</name><affiliation><nlm:aff id="aff1">Pharmaceutical Institute, Pharmaceutical Chemistry I,<institution>University of Bonn</institution>, An der Immenburg 4, D-53121 Bonn,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hayashi, Yoshio" sort="Hayashi, Yoshio" uniqKey="Hayashi Y" first="Yoshio" last="Hayashi">Yoshio Hayashi</name><affiliation><nlm:aff id="aff2">Department of Medicinal Chemistry,<institution>Tokyo University of Pharmacy and Life Sciences</institution>, Tokyo 192-0392,<country>Japan</country></nlm:aff></affiliation></author><author><name sortKey="Jung, Sang Hun" sort="Jung, Sang Hun" uniqKey="Jung S" first="Sang-Hun" last="Jung">Sang-Hun Jung</name><affiliation><nlm:aff id="aff3">College of Pharmacy and Institute of Drug Research and Development,<institution>Chungnam National University</institution>, Daejeon 34134,<country>South Korea</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26878082</idno><idno type="pmc">7075650</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075650</idno><idno type="RBID">PMC:7075650</idno><idno type="doi">10.1021/acs.jmedchem.5b01461</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000037</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000037</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">An Overview of
Severe Acute Respiratory Syndrome–Coronavirus
(SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule
Chemotherapy</title><author><name sortKey="Pillaiyar, Thanigaimalai" sort="Pillaiyar, Thanigaimalai" uniqKey="Pillaiyar T" first="Thanigaimalai" last="Pillaiyar">Thanigaimalai Pillaiyar</name><affiliation><nlm:aff id="aff1">Pharmaceutical Institute, Pharmaceutical Chemistry I,<institution>University of Bonn</institution>, An der Immenburg 4, D-53121 Bonn,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Manickam, Manoj" sort="Manickam, Manoj" uniqKey="Manickam M" first="Manoj" last="Manickam">Manoj Manickam</name><affiliation><nlm:aff id="aff3">College of Pharmacy and Institute of Drug Research and Development,<institution>Chungnam National University</institution>, Daejeon 34134,<country>South Korea</country></nlm:aff></affiliation></author><author><name sortKey="Namasivayam, Vigneshwaran" sort="Namasivayam, Vigneshwaran" uniqKey="Namasivayam V" first="Vigneshwaran" last="Namasivayam">Vigneshwaran Namasivayam</name><affiliation><nlm:aff id="aff1">Pharmaceutical Institute, Pharmaceutical Chemistry I,<institution>University of Bonn</institution>, An der Immenburg 4, D-53121 Bonn,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hayashi, Yoshio" sort="Hayashi, Yoshio" uniqKey="Hayashi Y" first="Yoshio" last="Hayashi">Yoshio Hayashi</name><affiliation><nlm:aff id="aff2">Department of Medicinal Chemistry,<institution>Tokyo University of Pharmacy and Life Sciences</institution>, Tokyo 192-0392,<country>Japan</country></nlm:aff></affiliation></author><author><name sortKey="Jung, Sang Hun" sort="Jung, Sang Hun" uniqKey="Jung S" first="Sang-Hun" last="Jung">Sang-Hun Jung</name><affiliation><nlm:aff id="aff3">College of Pharmacy and Institute of Drug Research and Development,<institution>Chungnam National University</institution>, Daejeon 34134,<country>South Korea</country></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Medicinal Chemistry</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="jm5b01461_0045" id="ab-tgr1"></graphic></p><p>Severe
acute respiratory syndrome (SARS) is caused by a newly emerged
coronavirus that infected more than 8000 individuals and resulted
in more than 800 (10–15%) fatalities in 2003. The causative
agent of SARS has been identified as a novel human coronavirus (SARS-CoV),
and its viral protease, SARS-CoV 3CL<sup>pro</sup>, has been shown
to be essential for replication and has hence been recognized as a
potent drug target for SARS infection. Currently, there is no effective
treatment for this epidemic despite the intensive research that has
been undertaken since 2003 (over 3500 publications). This perspective
focuses on the status of various efficacious anti-SARS-CoV 3CL<sup>pro</sup> chemotherapies discovered during the last 12 years (2003–2015)
from all sources, including laboratory synthetic methods, natural
products, and virtual screening. We describe here mainly peptidomimetic
and small molecule inhibitors of SARS-CoV 3CL<sup>pro</sup>. Attempts
have been made to provide a complete description of the structural
features and binding modes of these inhibitors under many conditions.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cheever, F S" uniqKey="Cheever F">F. S. Cheever</name></author><author><name sortKey="Daniels, J B" uniqKey="Daniels J">J. B. Daniels</name></author><author><name sortKey="Pappenheimer, A M" uniqKey="Pappenheimer A">A. M. Pappenheimer</name></author><author><name sortKey="Baily, O T" uniqKey="Baily O">O. T. Baily</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bailey, O T" uniqKey="Bailey O">O. T. Bailey</name></author><author><name sortKey="Pappenheimer, A M" uniqKey="Pappenheimer A">A. M. Pappenheimer</name></author><author><name sortKey="Sargent, F" uniqKey="Sargent F">F. Sargent</name></author><author><name sortKey="Cheever, M D" uniqKey="Cheever M">M. D. Cheever</name></author><author><name sortKey="Daniels, J B" uniqKey="Daniels J">J. B. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Chem</journal-id><journal-id journal-id-type="publisher-id">jm</journal-id><journal-id journal-id-type="coden">jmcmar</journal-id><journal-title-group><journal-title>Journal of Medicinal Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn><publisher><publisher-name>American Chemical
Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26878082</article-id><article-id pub-id-type="pmc">7075650</article-id><article-id pub-id-type="doi">10.1021/acs.jmedchem.5b01461</article-id><article-categories><subj-group><subject>Perspective</subject></subj-group></article-categories><title-group><article-title>An Overview of
Severe Acute Respiratory Syndrome–Coronavirus
(SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule
Chemotherapy</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" id="ath1"><name><surname>Pillaiyar</surname><given-names>Thanigaimalai</given-names></name><xref rid="cor1" ref-type="other">*</xref><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath2"><name><surname>Manickam</surname><given-names>Manoj</given-names></name><xref rid="aff3" ref-type="aff">∥</xref></contrib><contrib contrib-type="author" id="ath3"><name><surname>Namasivayam</surname><given-names>Vigneshwaran</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath4"><name><surname>Hayashi</surname><given-names>Yoshio</given-names></name><xref rid="aff2" ref-type="aff">§</xref></contrib><contrib contrib-type="author" id="ath5"><name><surname>Jung</surname><given-names>Sang-Hun</given-names></name><xref rid="aff3" ref-type="aff">∥</xref></contrib><aff id="aff1"><label>†</label>Pharmaceutical Institute, Pharmaceutical Chemistry I,<institution>University of Bonn</institution>, An der Immenburg 4, D-53121 Bonn,<country>Germany</country></aff><aff id="aff2"><label>§</label>Department of Medicinal Chemistry,<institution>Tokyo University of Pharmacy and Life Sciences</institution>, Tokyo 192-0392,<country>Japan</country></aff><aff id="aff3"><label>∥</label>College of Pharmacy and Institute of Drug Research and Development,<institution>Chungnam National University</institution>, Daejeon 34134,<country>South Korea</country></aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>Phone: <phone>+49-228-73-2360</phone>. E-mail: <email>thanigai@uni-bonn.de</email>.</corresp></author-notes><pub-date pub-type="epub"><day>15</day><month>02</month><year>2016</year></pub-date><pub-date pub-type="ppub"><day>28</day><month>07</month><year>2016</year></pub-date><volume>59</volume><issue>14</issue><fpage>6595</fpage><lpage>6628</lpage><history><date date-type="received"><day>19</day><month>09</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2016 American Chemical Society</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>American Chemical Society</copyright-holder><license license-type="open-access"><license-p>This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract><p content-type="toc-graphic"><graphic xlink:href="jm5b01461_0045" id="ab-tgr1"></graphic></p><p>Severe
acute respiratory syndrome (SARS) is caused by a newly emerged
coronavirus that infected more than 8000 individuals and resulted
in more than 800 (10–15%) fatalities in 2003. The causative
agent of SARS has been identified as a novel human coronavirus (SARS-CoV),
and its viral protease, SARS-CoV 3CL<sup>pro</sup>, has been shown
to be essential for replication and has hence been recognized as a
potent drug target for SARS infection. Currently, there is no effective
treatment for this epidemic despite the intensive research that has
been undertaken since 2003 (over 3500 publications). This perspective
focuses on the status of various efficacious anti-SARS-CoV 3CL<sup>pro</sup> chemotherapies discovered during the last 12 years (2003–2015)
from all sources, including laboratory synthetic methods, natural
products, and virtual screening. We describe here mainly peptidomimetic
and small molecule inhibitors of SARS-CoV 3CL<sup>pro</sup>. Attempts
have been made to provide a complete description of the structural
features and binding modes of these inhibitors under many conditions.</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>jm5b01461</meta-value></custom-meta><custom-meta><meta-name>document-id-new-14</meta-name><meta-value>jm5b01461</meta-value></custom-meta><custom-meta><meta-name>ccc-price</meta-name><meta-value></meta-value></custom-meta></custom-meta-group></article-meta><notes id="notes-d1e21-autogenerated"><fn-group><fn fn-type="" id="d30e170"><p>This article is made available for a limited time sponsored by ACS under the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/page/policy/freetoread/index.html">ACS Free to Read License</ext-link>, which permits copying and redistribution of the article for non-commercial scholarly purposes.</p></fn></fn-group></notes></front><body><sec id="sec1"><label>1</label><title>Introduction</title><p>Coronaviruses
have been known for more than five decades since
the first prototype murine strain, JHM, was reported in 1947.<sup><xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref2">2</xref></sup> Viruses such as porcine transmissible gastroenteritis virus (TGEV),
avian infectious bronchitis virus (IBV), and bovine coronavirus (BCoV)
severely infect animals. The murine coronavirus mouse hepatitis virus
(MHV) was studied as a model for the human disease. Although studies
of the mechanism of replication as well as the pathogenesis of several
coronaviruses have been very active since 1970s, this family of coronaviruses
received much attention when it was recognized that a new human coronavirus
was responsible for severe acute respiratory syndrome (SARS), a contagious
and fatal illness.<sup><xref ref-type="bibr" rid="ref3">3</xref>,<xref ref-type="bibr" rid="ref4">4</xref></sup></p><p>Coronaviruses belong to
one of two subfamilies of (<italic>Coronavirinae</italic> and <italic>Torovirinae</italic>) of the family <italic>Coronaviridae</italic>, which in turn comprise the order <italic>Nidovirales</italic> (<xref rid="fig1" ref-type="fig">Figure <xref rid="fig1" ref-type="fig">1</xref></xref>).<sup><xref ref-type="bibr" rid="ref5">5</xref>,<xref ref-type="bibr" rid="ref6">6</xref></sup> They
are classified into four genera (α, β, γ, and δ),
and each genus can be further divided into lineage subgroups. SARS-CoV
belongs to the <italic>Betacoronavirus</italic> group (see <xref rid="fig1" ref-type="fig">Figure <xref rid="fig1" ref-type="fig">1</xref></xref>).</p><fig id="fig1" position="float"><label>Figure 1</label><caption><p>Schematic representation
of the taxonomy of <italic>Coronaviridae</italic> (according to the
International Committee on Taxonomy of Viruses).
SARS-CoV belongs to the <italic>Betacoronavirus</italic> family but
has a “b” lineage. *<italic>Coronaviridae</italic>,
along with <italic>Arteriviridae</italic>, <italic>Mesoniviridae</italic>, and <italic>Roniviridae</italic>, are members of this family.</p></caption><graphic xlink:href="jm5b01461_0002" id="gr1" position="float"></graphic></fig><p>In 2003, a new human coronavirus
was identified as an etiological
agent of the first global pandemic of the 21st century, severe-acute
respiratory syndrome (SARS), and the virus was named SARS-CoV. The
first case of “an atypical pneumonia” was reported in
China during November 2002.<sup><xref ref-type="bibr" rid="ref7">7</xref></sup> Its rapid
and unexpected spread to another 29 countries, mostly in Asia and
North America, alarmed both the public and World Health Organization
(WHO). Within a few months of this outbreak in 2003, the WHO announced
in a cumulative report about its emergence that it had caused 916
deaths among 8422 cases (fatality rate of 10–15%) worldwide,
as shown in <xref rid="tbl1" ref-type="other">Table <xref rid="tbl1" ref-type="other">1</xref></xref>.<sup><xref ref-type="bibr" rid="ref8">8</xref></sup> This incidence indicates how rapidly
a contagious illness can spread in this highly interconnected society.</p><table-wrap id="tbl1" position="float"><label>Table 1</label><caption><title>Summary of SARS Cases by Country or
Area, November 1, 2002 to August 7, 2003</title></caption><table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col></colgroup><thead><tr><th style="border:none;" align="center"> </th><th colspan="3" align="center">cumulative
number of cases<hr></hr></th><th style="border:none;" align="center"> </th><th colspan="4" align="center">status<hr></hr></th><th style="border:none;" align="center"> </th><th style="border:none;" align="center"> </th><th style="border:none;" align="center"> </th><th style="border:none;" align="center"> </th></tr><tr><th style="border:none;" align="center">country/areas</th><th style="border:none;" align="center">F<xref rid="t1fn1" ref-type="table-fn">a</xref></th><th style="border:none;" align="center">M<xref rid="t1fn1" ref-type="table-fn">a</xref></th><th style="border:none;" align="center">T<xref rid="t1fn1" ref-type="table-fn">a</xref></th><th style="border:none;" align="center">median
age
(range)</th><th style="border:none;" align="center">no. of cases
hospitalized</th><th style="border:none;" align="center">no. of cases
recovered</th><th style="border:none;" align="center">no. of deaths</th><th style="border:none;" align="center">CFR<xref rid="t1fn2" ref-type="table-fn">b</xref> (%)</th><th style="border:none;" align="center">no. of imported
cases (%)</th><th style="border:none;" align="center">no. of HCW
affected (%)<xref rid="t1fn3" ref-type="table-fn">c</xref></th><th style="border:none;" align="center">date
onset
first probable case</th><th style="border:none;" align="center">date onset
last probable case</th></tr></thead><tbody><tr><td style="border:none;" align="left">Australia</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">6</td><td style="border:none;" align="left">15 (1–45)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">6</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">6 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">24-Mar-03</td><td style="border:none;" align="left">1-Apr-03</td></tr><tr><td style="border:none;" align="left">Brazil</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left"> </td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">3-Apr-03</td><td style="border:none;" align="left">3-Apr-03</td></tr><tr><td style="border:none;" align="left">Canada</td><td style="border:none;" align="left">151</td><td style="border:none;" align="left">100</td><td style="border:none;" align="left">251</td><td style="border:none;" align="left">49 (1–98)</td><td style="border:none;" align="left">10</td><td style="border:none;" align="left">200</td><td style="border:none;" align="left">41</td><td style="border:none;" align="left">17</td><td style="border:none;" align="left">5 (2)</td><td style="border:none;" align="left">108 (43)</td><td style="border:none;" align="left">23-Feb-03</td><td style="border:none;" align="left">12-Jun-03</td></tr><tr><td style="border:none;" align="left">China</td><td style="border:none;" align="left">P</td><td style="border:none;" align="left">P</td><td style="border:none;" align="left">5327</td><td style="border:none;" align="left">P</td><td style="border:none;" align="left">29</td><td style="border:none;" align="left">4949</td><td style="border:none;" align="left">349</td><td style="border:none;" align="left">7</td><td style="border:none;" align="left">NA</td><td style="border:none;" align="left">1002 (19)</td><td style="border:none;" align="left">16-Nov-02</td><td style="border:none;" align="left">25-Jun-03</td></tr><tr><td style="border:none;" align="left">Hong Kong</td><td style="border:none;" align="left">977</td><td style="border:none;" align="left">778</td><td style="border:none;" align="left">1755</td><td style="border:none;" align="left">40 (0–100)</td><td style="border:none;" align="left">7</td><td style="border:none;" align="left">1448</td><td style="border:none;" align="left">300</td><td style="border:none;" align="left">17</td><td style="border:none;" align="left">NA</td><td style="border:none;" align="left">386 (22)</td><td style="border:none;" align="left">15-Feb-03</td><td style="border:none;" align="left">31-May-03</td></tr><tr><td style="border:none;" align="left">Macao</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">28</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">5-May-03</td><td style="border:none;" align="left">5-May-03</td></tr><tr><td style="border:none;" align="left">Taiwan</td><td style="border:none;" align="left">349<xref rid="t1fn4" ref-type="table-fn">d</xref></td><td style="border:none;" align="left">319<xref rid="t1fn4" ref-type="table-fn">d</xref></td><td style="border:none;" align="left">665</td><td style="border:none;" align="left">46 (2–79)</td><td style="border:none;" align="left">10</td><td style="border:none;" align="left">475</td><td style="border:none;" align="left">180</td><td style="border:none;" align="left">27</td><td style="border:none;" align="left">50 (8)</td><td style="border:none;" align="left">86 (13)</td><td style="border:none;" align="left">25-Feb-03</td><td style="border:none;" align="left">15-Jun-03</td></tr><tr><td style="border:none;" align="left">Colombia</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">28</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">2-Apr-03</td><td style="border:none;" align="left">2-Apr-03</td></tr><tr><td style="border:none;" align="left">Finland</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">24</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">30-Apr-03</td><td style="border:none;" align="left">30-Apr-03</td></tr><tr><td style="border:none;" align="left">France</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">6</td><td style="border:none;" align="left">7</td><td style="border:none;" align="left">49 (26–61)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">6</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">14</td><td style="border:none;" align="left">7 (100)</td><td style="border:none;" align="left">2 2 (29)</td><td style="border:none;" align="left">21-Mar-03</td><td style="border:none;" align="left">3-May-03</td></tr><tr><td style="border:none;" align="left">Germany</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">5</td><td style="border:none;" align="left">9</td><td style="border:none;" align="left">44 (4–73)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">9</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">9 (100)</td><td style="border:none;" align="left">1 (11)</td><td style="border:none;" align="left">9-Mar-03</td><td style="border:none;" align="left">6-May-03</td></tr><tr><td style="border:none;" align="left">India</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">25 (25–30)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">25-Apr-03</td><td style="border:none;" align="left">6-May-03</td></tr><tr><td style="border:none;" align="left">Indonesia</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">56 (47–65)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">2 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">6-Apr-03</td><td style="border:none;" align="left">17-Apr-03</td></tr><tr><td style="border:none;" align="left">Italy</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">30.5 (25–54)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">4 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">12-Mar-03</td><td style="border:none;" align="left">20-Apr-03</td></tr><tr><td style="border:none;" align="left">Kuwait</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">50</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">9-Apr-03</td><td style="border:none;" align="left">9-Apr-03</td></tr><tr><td style="border:none;" align="left">Malaysia</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">5</td><td style="border:none;" align="left">30 (26–84)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">40</td><td style="border:none;" align="left">5 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">14-Mar-03</td><td style="border:none;" align="left">22-Apr-03</td></tr><tr><td style="border:none;" align="left">Mongolia</td><td style="border:none;" align="left">8</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">9</td><td style="border:none;" align="left">32 (17–63)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">9</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">8 (89)</td><td style="border:none;" align="left">1 (11)</td><td style="border:none;" align="left">31-Mar-03</td><td style="border:none;" align="left">6-May-03</td></tr><tr><td style="border:none;" align="left">New Zealand</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">67</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left"> </td><td style="border:none;" align="left">20-Apr-03</td><td style="border:none;" align="left">20-Apr-03</td></tr><tr><td style="border:none;" align="left">Philippines</td><td style="border:none;" align="left">8</td><td style="border:none;" align="left">6</td><td style="border:none;" align="left">14</td><td style="border:none;" align="left">41 (29–73)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">12</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">14</td><td style="border:none;" align="left">7 (50)</td><td style="border:none;" align="left">4 (29)</td><td style="border:none;" align="left">25-Feb-03</td><td style="border:none;" align="left">5-May-03</td></tr><tr><td style="border:none;" align="left">Republic of Ireland</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">56</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">27-Feb-03</td><td style="border:none;" align="left">27-Feb-03</td></tr><tr><td style="border:none;" align="left">Republic of Korea</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">40 (20–80)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">25-Apr-03</td><td style="border:none;" align="left">10-May-03</td></tr><tr><td style="border:none;" align="left">Romania</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">52</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">19-Mar-03</td><td style="border:none;" align="left">19-Mar-03</td></tr><tr><td style="border:none;" align="left">Russian Federation</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">25</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left"> </td><td style="border:none;" align="left">NA</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">5-May-03</td><td style="border:none;" align="left">5-May-03</td></tr><tr><td style="border:none;" align="left">Singapore</td><td style="border:none;" align="left">161</td><td style="border:none;" align="left">77</td><td style="border:none;" align="left">238</td><td style="border:none;" align="left">35 (1–90)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">205</td><td style="border:none;" align="left">33</td><td style="border:none;" align="left">14</td><td style="border:none;" align="left">8 (3)</td><td style="border:none;" align="left">97 (41)</td><td style="border:none;" align="left">25-Feb-03</td><td style="border:none;" align="left">5-May-03</td></tr><tr><td style="border:none;" align="left">South Africa</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">62</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">100</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">3-Apr-03</td><td style="border:none;" align="left">3-Apr-03</td></tr><tr><td style="border:none;" align="left">Spain</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">33</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">26-Mar-03</td><td style="border:none;" align="left">26-Mar-03</td></tr><tr><td style="border:none;" align="left">Sweden</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">33</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">3 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left"> </td><td style="border:none;" align="left"> </td></tr><tr><td style="border:none;" align="left">Switzerland</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">35</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">1 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">9-Mar-03</td><td style="border:none;" align="left">9-Mar-03</td></tr><tr><td style="border:none;" align="left">Thailand</td><td style="border:none;" align="left">5</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">9</td><td style="border:none;" align="left">42 (2–79)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">7</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">22</td><td style="border:none;" align="left">9 (100)</td><td style="border:none;" align="left">1 2 (11)</td><td style="border:none;" align="left">11-Mar-03</td><td style="border:none;" align="left">27-May-03</td></tr><tr><td style="border:none;" align="left">United Kingdom</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">2</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">59 (28–74)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">4</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">4 (100)</td><td style="border:none;" align="left">0 (0)</td><td style="border:none;" align="left">1-Mar-03</td><td style="border:none;" align="left">1-Apr-03</td></tr><tr><td style="border:none;" align="left">United States</td><td style="border:none;" align="left">16</td><td style="border:none;" align="left">17</td><td style="border:none;" align="left">33</td><td style="border:none;" align="left">36 (0–83)</td><td style="border:none;" align="left">7</td><td style="border:none;" align="left">26</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">31 (94)</td><td style="border:none;" align="left">1 (3)</td><td style="border:none;" align="left">9-Jan-03</td><td style="border:none;" align="left">13-Jul-03</td></tr><tr><td style="border:none;" align="left">Vietnam</td><td style="border:none;" align="left">39</td><td style="border:none;" align="left">24</td><td style="border:none;" align="left">63</td><td style="border:none;" align="left">43 (20–76)</td><td style="border:none;" align="left">0</td><td style="border:none;" align="left">58</td><td style="border:none;" align="left">5</td><td style="border:none;" align="left">8</td><td style="border:none;" align="left">1 (2)</td><td style="border:none;" align="left">36 (57)</td><td style="border:none;" align="left">23-Feb-0</td><td style="border:none;" align="left">14-Apr-03</td></tr></tbody></table><table-wrap-foot><fn id="t1fn1"><label>a</label><p>Note: F, female; M, male; P, pending;
T, total.</p></fn><fn id="t1fn2"><label>b</label><p>Case fatality
based on cases with
known outcome and irrespective of immediate cause of death.</p></fn><fn id="t1fn3"><label>c</label><p>Health care worker (HCW).</p></fn><fn id="t1fn4"><label>d</label><p>Discarding of three cases, new breakdown
by sex pending.</p></fn></table-wrap-foot></table-wrap><p>SARS is
mainly characterized by a high fever (>38 °C), dyspnea,
lymphopenia, headache, and lower respiratory tract infections;<sup><xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref10">10</xref></sup> concurrent gastrointestinal symptoms and diarrhea are also common.<sup><xref ref-type="bibr" rid="ref11">11</xref>−<xref ref-type="bibr" rid="ref13">13</xref></sup> With the enormous efforts of the WHO and expert scientists from
various countries, a novel human coronavirus was identified as the
etiological agent for SARS.<sup><xref ref-type="bibr" rid="ref4">4</xref>,<xref ref-type="bibr" rid="ref14">14</xref></sup> The sequence information
on the coronavirus polymerase gene, along with all other previously
characterized strains, demonstrated that this was a previously unrecognized
coronavirus in humans.<sup><xref ref-type="bibr" rid="ref3">3</xref>,<xref ref-type="bibr" rid="ref15">15</xref>−<xref ref-type="bibr" rid="ref17">17</xref></sup> Although the
SARS epidemic was successfully controlled in 2003,<sup><xref ref-type="bibr" rid="ref18">18</xref>,<xref ref-type="bibr" rid="ref19">19</xref></sup> the identification of animal reservoirs for this virus and the recent
report of a new virus related to SARS, called Middle East respiratory
syndrome (MERS),<sup><xref ref-type="bibr" rid="ref20">20</xref></sup> provide strong motivation
for the development of anti-SARS agents to treat this potentially
fatal respiratory illness.</p><p>The recent outbreak of MERS in South
Korea alarmed the public,
and the number of patients under quarantine was reported to be 1600.<sup><xref ref-type="bibr" rid="ref21">21</xref></sup> After the first patient was diagnosed with MERS
on May 20, 2015, within a period of two months, the total number of
cases identified had increased to 186 with 36 fatalities and possible
infection of 16700 individuals who were subjected to isolation.<sup><xref ref-type="bibr" rid="ref22">22</xref>,<xref ref-type="bibr" rid="ref23">23</xref></sup> By the end of August 2015, a total of 1511 patients were infected
worldwide with this virus, of which 574 (∼39%) had died after
the first case was recorded in June 2012 in Saudi Arabia.<sup><xref ref-type="bibr" rid="ref24">24</xref></sup></p><p>To date, the FDA has not approved an antiviral
agent for the treatment
of SARS, although the clinical treatments are directed toward symptomatic
relief. Therefore, the development of effective antiviral chemotherapy
against SARS-CoV is important for future outbreaks. Numerous reports
(over 3500 publications) have been published on SARS-CoV since 2002.
Recently, a brief review on the progress of anti-SARS chemotherapy
was reported.<sup><xref ref-type="bibr" rid="ref25">25</xref></sup> However; no reports have
been published about the substrate selectivity, mechanism of action,
and SARs of the inhibitors. Therefore, to overcome the drawbacks and
to enhance the qualitative understanding of the etiology, pathology,
and possible therapeutic targets against this virus, a comprehensive
review is currently needed.</p><p>This perspective focuses on the
status of SARS-CoV 3 chymotrypsin-like
protease (3CL<sup>pro</sup>) inhibitors discovered during last 12
years from all sources, including laboratory synthetic methods, natural
products, virtual screening, and structure-based molecular docking
studies. Attempts have been made to provide a complete description
of the structural features (SARs) and detailed mechanisms of action
of inhibitors. We believe that this perspective will comprise a cumulative
source of SARS-CoV 3CL<sup>pro</sup> inhibitors for researchers and
further the understanding of anti-SARS chemotherapy.</p></sec><sec id="sec2"><label>2</label><title>SARS-CoV and Structure of 3CL<sup>pro</sup></title><p>Coronaviruses are a family of positive strand,
enveloped RNA viruses
that can cause acute and chronic respiratory, enteric, and central
nervous system diseases in many species of animals, including humans.<sup><xref ref-type="bibr" rid="ref26">26</xref>,<xref ref-type="bibr" rid="ref27">27</xref></sup> This family features the largest viral genomes (27–31 kb)
found to date.<sup><xref ref-type="bibr" rid="ref28">28</xref>,<xref ref-type="bibr" rid="ref29">29</xref></sup> The genomic RNA is complexed
with the basic nucleocapsid (N) protein to form a helical capsid within
the membrane. The membrane of all coronaviruses is comprised of a
minimum of three viral proteins: (i) a spike protein (S), a type of
glycoprotein I, (ii) a membrane protein (M) that spans the membrane,
and (iii) an envelope protein (E), a highly hydrophobic protein that
covers the entire structure of the coronavirus (<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref></xref>).<sup><xref ref-type="bibr" rid="ref30">30</xref></sup> The SARS-CoV
genome contains two open reading frames, connected by a ribosomal
frame shift, which encode two large overlapping replicase polyproteins,
pp1a (∼450 kDa) and pp1ab (∼750 kDa), from which the
functional proteins are produced by an extensive proteolytic process.<sup><xref ref-type="bibr" rid="ref31">31</xref>,<xref ref-type="bibr" rid="ref32">32</xref></sup> While other coronaviruses utilize three proteases for proteolytic
processing, the SARS-CoV is known to encode only two proteases, which
include a papain-like cysteine protease (PL<sup>pro</sup>)<sup><xref ref-type="bibr" rid="ref33">33</xref></sup> and a chymotrypsin-like cysteine protease known
as 3C-like protease (3CL<sup>pro</sup>).<sup><xref ref-type="bibr" rid="ref34">34</xref>−<xref ref-type="bibr" rid="ref39">39</xref></sup> The 3CL<sup>pro</sup> enzyme, also called Main protease (M<sup>pro</sup>), is indispensable to the viral replication and infection process,
thereby making it an ideal target for antiviral therapy.</p><fig id="fig2" position="float"><label>Figure 2</label><caption><p>Structure of
a coronavirus showing proteins used for replication.</p></caption><graphic xlink:href="jm5b01461_0003" id="gr2" position="float"></graphic></fig><p>The X-ray crystallographic structure of hexapeptidyl
chlromethyl
ketone (CMK) inhibitor bound to 3CL<sup>pro</sup> at different pH
values was solved by Yang et al. in 2003 (see <xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref></xref>).<sup><xref ref-type="bibr" rid="ref38">38</xref></sup> It was explained
that SARS-CoV 3CL<sup>pro</sup> forms as a dimer with the two promoters
(denoted as “A” and “B”) oriented almost
at right angles to each other (<xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref></xref>A,B). The crystal structure of the SARS-CoV 3CL<sup>pro</sup>, similar those of other 3CL<sup>pro</sup>, comprises three
domains. Domains I (residues 8–101) and II (residues 102–184)
contain β-barrels that form the chymotrypsin structure, whereas
domain III (residues 201–306) consists mainly of α-helices
(<xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref></xref>).<sup><xref ref-type="bibr" rid="ref38">38</xref>−<xref ref-type="bibr" rid="ref40">40</xref></sup> SARS-CoV 3CL<sup>pro</sup> has a Cys-His catalytic dyad, and the
substrate or inhibitor binding site is located in a cleft between
domain I and II. The substrate-binding subsite S1 specificity in protomer
A of a CoV protease confers absolute specificity for the P1-Gln substrate
residue on the enzyme. Each <italic>N</italic>-terminus residue (<italic>N</italic>-finger) squeezed between domains II and III of the parent
monomer and domain II of the other monomer, plays an important role
in dimerization and formation of the active site of 3CL<sup>pro</sup>. The SARS-CoV 3CL<sup>pro</sup> dimer is highly active, while the
monomer is principally inactive.<sup><xref ref-type="bibr" rid="ref41">41</xref></sup></p><fig id="fig3" position="float"><label>Figure 3</label><caption><p>SARS-CoV 3CL<sup>pro</sup> dimer structure complexed with a substrate-analogue
hexapeptidyl CMK inhibitor (PDB ID 1UK4).<sup><xref ref-type="bibr" rid="ref38">38</xref></sup> (A) SARS-CoV
3CL<sup>pro</sup> dimer structure is presented as ribbons, and inhibitor
molecules are shown as ball-and-stick models. Protomer A (the catalytically
competent enzyme) is shown in red, protomer B (the inactive enzyme)
is shown in blue, and the inhibitor molecules are shown in yellow.
The <italic>N</italic>-finger residues of protomer B are shown in
green. The molecular surface of the dimer is superimposed. (B) Cartoon
diagram illustrating the important role of the <italic>N</italic>-finger
in both the dimerization and maintenance of the active form of the
enzyme is shown. Adapted from Yang, H. et al. (permission Copyright
(2003) National Academy of Sciences, U.S.A.<sup><xref ref-type="bibr" rid="ref38">38</xref></sup></p></caption><graphic xlink:href="jm5b01461_0004" id="gr3" position="float"></graphic></fig></sec><sec id="sec3"><label>3</label><title>SARS-CoV 3CL<sup>pro</sup> Inhibitors</title><p>In 2004,
Kua et al. reported the first preparation of the fully
active dimeric SARS-CoV 3CL<sup>pro</sup> with the authentic sequence.<sup><xref ref-type="bibr" rid="ref42">42</xref></sup> To screen for inhibitors of SARS-CoV 3CL<sup>pro</sup>, they prepared a peptide substrate with a fluorescence
quenching pair 4-(4-dimethylaminophenylazo)benzoic acid (Dabcyl) and
5-[(2-aminoethyl)amino]naphthalene-1-sulfonic acid (Edans) at the <italic>N</italic>- and <italic>C</italic>-termini, respectively, which resulted
extremely sensitive assay and allowed many potent inhibitors of SARS-CoV
3CL<sup>pro</sup> to be identified.</p><p>3CL<sup>pro</sup> are cysteine
proteases, which are analogues to
the main picornavirus 3C protease, a family of viruses that also cause
respiratory illness. The conservation of specificities within the
3CL<sup>pro</sup> family of coronaviruses has been reported with the
amino acid sequence Leu-Gln-Ser or Leu-Gly-Ala as the preferred P2–P1–P1′
sequence (<xref rid="tbl2" ref-type="other">Table <xref rid="tbl2" ref-type="other">2</xref></xref>).<sup><xref ref-type="bibr" rid="ref1">1</xref></sup> Although the functional similarities of 3CL<sup>pro</sup> have “cleavage site-specificity” to that
of picornavirus 3C proteases, the structural similarities between
the two families are limited.<sup><xref ref-type="bibr" rid="ref43">43</xref></sup> The SARS-CoV
3CL<sup>pro</sup> cleaves polyproteins at no less than 11 conserved
sites involving the Leu-Gln↓(Ser, Ala, Gly) sequence, which
appears to be a conserved pattern of the 3CL<sup>pro</sup> of SARS-CoV.<sup><xref ref-type="bibr" rid="ref3">3</xref>,<xref ref-type="bibr" rid="ref37">37</xref></sup> The active site of SARS-CoV 3CL<sup>pro</sup> contains Cys145 and
His41, creating a catalytic dyad in which the cysteine functions as
a common nucleophile in the proteolytic process (<xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref></xref>).<sup><xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref43">43</xref>,<xref ref-type="bibr" rid="ref44">44</xref></sup></p><table-wrap id="tbl2" position="float"><label>Table 2</label><caption><title>Predicted Cleavage
Sites by SARS-CoV
3CL<sup>pro</sup></title></caption><table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col><col align="left"></col></colgroup><thead><tr><th style="border:none;" align="center">P4P3P2P1–P1′P2′P3P4′</th><th style="border:none;" align="center">proteins<xref rid="t2fn1" ref-type="table-fn">a</xref></th></tr></thead><tbody><tr><td style="border:none;" align="left">AVLQ-SGFR</td><td style="border:none;" align="left">TM2/3CL<sup>pro</sup></td></tr><tr><td style="border:none;" align="left">VTFQ-GKFK</td><td style="border:none;" align="left">3CL<sup>pro</sup>/TM3</td></tr><tr><td style="border:none;" align="left">ATVQ-SKMS</td><td style="border:none;" align="left">TM3/?</td></tr><tr><td style="border:none;" align="left">ATLQ-AIAS</td><td style="border:none;" align="left">?</td></tr><tr><td style="border:none;" align="left">VKLQ-NNEL</td><td style="border:none;" align="left">?</td></tr><tr><td style="border:none;" align="left">VRLQ-AGNA</td><td style="border:none;" align="left">?/GFL</td></tr><tr><td style="border:none;" align="left">PLMQ-SADA</td><td style="border:none;" align="left">GFL/?</td></tr><tr><td style="border:none;" align="left">TVLG-AVGA</td><td style="border:none;" align="left">?/RdRp</td></tr><tr><td style="border:none;" align="left">ATLQ-AENV</td><td style="border:none;" align="left">RdRp/NTPase, etc.</td></tr><tr><td style="border:none;" align="left">TRLQ-SLEN</td><td style="border:none;" align="left">NTPase, etc./exonuclease</td></tr><tr><td style="border:none;" align="left">PKLQ-ASQA</td><td style="border:none;" align="left">exonuclease/2′-<italic>O</italic>-MT</td></tr></tbody></table><table-wrap-foot><fn id="t2fn1"><label>a</label><p>TM, Transmembrane;
GFL, growth factor-like
domain; RdRp, RNA-dependent RNA polymerase; 2′-<italic>O</italic>-MT, 2′-<italic>O</italic>-methyltransferase.</p></fn></table-wrap-foot></table-wrap><fig id="fig4" position="float"><label>Figure 4</label><caption><p>Natural amide substrate hydrolysis by Cys145
and His41 at the active
site of 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0005" id="gr4" position="float"></graphic></fig><p>The initial step in the process is deprotonation of Cys-thiol
(I)
and followed by nucleophilic attack of resulting anionic sulfur on
the substrate carbonyl carbon(II). In this step, a peptide product
is released that has an amine terminus, while histidine is restored
its deprotonated form (III). In the next step, the resulting thioester
is hydrolyzed (IV) to release a carboxylic acid, and the free enzyme
(V) is regenerated in the final step. Therefore, the functional significance
of 3CL<sup>pro</sup> in the viral life cycle makes this protease an
ideal target for the development of drugs against SARS and other coronavirus
infections.</p><p>In 2003, the first X-ray structure of the SARS-3CL<sup>pro</sup> dimer with a peptidic CMK (<bold>1</bold>; Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK,
see <xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref>) inhibitor
was elucidated (Yang, H. et al.).<sup><xref ref-type="bibr" rid="ref38">38</xref></sup> The
unexpected binding mode of the substrate–analogue <bold>1</bold> provides a structural explanation for the P1-Gln entering into the
specific pocket and for the decreased P2-Leu specificity of the SARS
enzyme. However, specificities for P2-Leu and P4-Ser have been observed
in the structure of <bold>1</bold> bound to TGEV 3CL<sup>pro</sup>,<sup><xref ref-type="bibr" rid="ref43">43</xref></sup> whereas P3-Thr is orientated toward
bulk solvents. In addition, compound <bold>2</bold> or rupintrivir
(AG7088)<sup><xref ref-type="bibr" rid="ref43">43</xref></sup> shown in <xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref> has already been clinically tested for common
cold (targeting rhinovirus 3C protease) binds to human rhinovirus
3C protease in the same orientation as that observed for the CMK inhibitor
of TGEV. The X-ray crystal structure of <bold>1</bold> with TGEV 3CL<sup>pro</sup> and superimposed <bold>2</bold> (AG7088) with HRV2 3C<sup>pro</sup> is depicted in <xref rid="fig6" ref-type="fig">Figure <xref rid="fig6" ref-type="fig">6</xref></xref>.</p><fig id="fig5" position="float"><label>Figure 5</label><caption><p>Chemical structures of inhibitors <bold>1</bold>, <bold>2</bold>, and <bold>3</bold>.</p></caption><graphic xlink:href="jm5b01461_0006" id="gr5" position="float"></graphic></fig><fig id="fig6" position="float"><label>Figure 6</label><caption><p>(A) The crystal structure of <bold>1</bold> with TGEV 3CL<sup>pro</sup> (PDB ID 1P9U) and superimposed <bold>2</bold> with HRV2 3C<sup>pro</sup> (PDB
ID 1CQQ). The
protein binding pocket is shown in surface representation (pink color).
The carbon color of compounds <bold>1</bold> (B), <bold>2</bold> (C),
and the binding pocket residues of TGEV 3CL<sup>pro</sup> and HRV2
3C<sup>pro</sup> are represented in magenta, green, and dark- and
light-gray, respectively. Oxygen atoms are colored in red, nitrogen
atoms in blue, sulfur atoms in yellow and hydrogen atoms in white.</p></caption><graphic xlink:href="jm5b01461_0007" id="gr6" position="float"></graphic></fig><p>Because the substrate specificity
of picornavirus 3C<sup>pro</sup> for the P1–P1′ and
P4 sites is very similar to that
of coronavirus 3CL<sup>pro</sup>, compounds <bold>1</bold> and <bold>2</bold> have been proposed as a starting point in the development
of new SARS-CoV 3CL<sup>pro</sup> inhibitors (<xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref>).<sup><xref ref-type="bibr" rid="ref45">45</xref>−<xref ref-type="bibr" rid="ref48">48</xref></sup> In addition, the HIV-1 protease inhibitor <bold>3</bold> (<xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref>)<sup><xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref49">49</xref></sup> was found to have high binding affinity toward SARS-CoV 3CL<sup>pro</sup> as well. Using the above three molecules as peptidomimetics,
many medicinal chemistry studies have been focused on developing a
potent chemotherapy method for SARS.</p><p>Drugs designed to treat
SARS-CoV 3CL<sup>pro</sup> can be broadly
classified into two types: (i) peptidic inhibitors, which mimic natural
peptide substrates, and (ii) small molecule-based inhibitors, obtained
from modifications of existing protease inhibitors, virtual screening,
structure-based molecular docking studies, and natural products. Additionally,
metal-conjugated inhibitors as well as some miscellaneous SARS-CoV
3CL<sup>pro</sup> inhibitors are also discussed in this perspective.</p></sec><sec id="sec4"><label>4</label><title>Peptidomimetic Inhibitors</title><p>In principle, a good substrate
can be converted to a good inhibitor
by replacement of a part of the substrate sequence that binds directly
to the active site of the protease (reversible or irreversible) with
the chemical “warhead” targeting the catalytic mechanism.
Peptidic inhibitors were designed by attaching a chemical “warhead”
type agent to a peptide that mimics the natural substrate. These warhead
groups include Michael acceptors, aldehydes, epoxy ketones, halomethyl
ketones, and several others (for example, see <xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref></xref>). Mechanistically, these inhibitors act
through a two-step procedure, wherein they first bind and form a noncovalent
complex with the enzyme such that the warhead is located in close
proximity to the catalytic residue. This is followed by a nucleophilic
attack by the catalytic cysteine and covalent bond formation. In this
perspective, the discussion of peptidomimetics is focused on the substrate
selectivity to each specific site (S1′–S1–S2–S3–S4)
of 3CL<sup>pro</sup>, mode of action, and SAR studies.</p><fig id="fig7" position="float"><label>Figure 7</label><caption><p>Proposed mechanism of
cysteine protease inactivation by inhibitors
containing Michael acceptor groups.</p></caption><graphic xlink:href="jm5b01461_0008" id="gr7" position="float"></graphic></fig><sec id="sec4.1"><label>4.1</label><title>Peptides with a Michael Acceptor</title><p>Peptidyl
or peptidomimetic derivatives contain Michael acceptors
as warheads and are an important class of cysteine protease inhibitors.
In general, inhibitor design strategies involve the replacement of
a substrate’s scissile amide bond with an appropriate Michael
acceptor group. The inactivation of a cysteine protease by a Michael
acceptor group is depicted in <xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref></xref>. The cysteine residue undergoes 1,4-addition to the
inhibitor at the Michael acceptor warhead group, and the subsequent
protonation of the α-carbanion results in the irreversible inhibition
of the enzyme.</p><p>The SAR study of compound <bold>2</bold> indicated
that the inhibitory activity was improved by replacing the following
side chain residues: the P1-lactam with a phenyl group (<bold>4</bold>) and the P2-fluorobenzyl with a benzyl group (<bold>5</bold>), as
shown in <xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref></xref>.<sup><xref ref-type="bibr" rid="ref50">50</xref></sup> It was noted that compound <bold>5</bold> had
two P1 and P2-phenylalanine groups and could fit in the S2 and S3
pockets of SARS-CoV 3CL<sup>pro</sup>, respectively. In addition,
the isoxazole moiety of these analogues adopted a conformation different
from that of inhibitor <bold>2</bold> and thus undergoes hydrogen
bonding with Gln192 in the S4 pocket. However, the conjugated ester
was not accessible (>4.5 Å) to Cys145 to allow a Michael addition
for covalent bond (C–S bond) formation. Consequently, this
process was achieved by a subsequent strategy using pseudo-<italic>C</italic>2 symmetric analogues (<bold>6</bold>–<bold>9</bold>, <xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref></xref>),<sup><xref ref-type="bibr" rid="ref50">50</xref></sup> thus exhibiting good inhibitory activity against
3CL<sup>pro</sup>. In particular, a compound comprised of Phe–Phe
dipeptide unsaturated ester and 4-(dimethylaminocinnamic acid) (<bold>8</bold>) exhibited potent inhibitory activity with an IC<sub>50</sub> value of approximately 1.0 μM and a <italic>K</italic><sub>i</sub> value of 0.52 μM. The cell-based bioassay gave an EC<sub>50</sub> = 0.18 μM. The presence of a 4-dimethylamino moiety
on the phenyl ring of these cinnamic analogues was found to be an
important structural functionality for activity enhancement.</p><fig id="fig8" position="float"><label>Figure 8</label><caption><p>Structural
modifications of compound <bold>2</bold> with a Michael
acceptor to produce active compounds <bold>4</bold>–<bold>15</bold>.</p></caption><graphic xlink:href="jm5b01461_0009" id="gr8" position="float"></graphic></fig><p>Another series of compounds were
reported based on the modification
of compound <bold>2</bold> at the P2 side chain by converting the <italic>p</italic>-fluorobenzyl group to a smaller benzyl (<bold>10</bold>) or prenyl group (<bold>11</bold>).<sup><xref ref-type="bibr" rid="ref51">51</xref></sup> These inhibitors (<bold>10</bold> and <bold>11</bold>) possess P1/P1′-Michael
acceptor groups, which can covalently link to the Cys145 (<xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref></xref>). The resulting
analogues are not only potential inhibitors of SARS-CoV 3CL<sup>pro</sup> (<italic>K</italic><sub>inact</sub> values) but are effective in
SARS-CoV cell-based bioassays. No toxicity was observed up to 100
μM. In addition, it was observed that compound <bold>12</bold>, which contains a hydroxyethylene isostere (<bold>12</bold>) in
place of the ketoethylene of compound <bold>10</bold>, was inactive
due to the loss of an important hydrogen bond interaction between
the backbone amide nitrogen of Glu166 and the carbonyl oxygen of the
inhibitor (<xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref></xref>).<sup><xref ref-type="bibr" rid="ref51">51</xref></sup> Further replacement of the P4-isoxazole
unit with a Boc-serine and a P2-benzyl, prenyl, or isobutyl (<bold>13</bold>–<bold>15</bold>: <xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref></xref>)<sup><xref ref-type="bibr" rid="ref52">52</xref></sup> increased
the inhibitory activity against 3CL<sup>pro</sup> to several times
of that of the lead inhibitor (<bold>2</bold>) (IC<sub>50</sub> =
800 μM), which confirmed both the P4-Boc-serine and P2-isopropyl
groups as important structural requirements for greater potency.</p><p>Although the activity of the potent analogue <bold>13</bold> was
improved to several times that of compound <bold>2</bold> against
SARS-CoV 3CL<sup>pro</sup>, substrate specificity for each site in
3CL<sup>pro</sup> could not be identified because the inhibitory activity
was absolutely dependent on the other residues in these peptides.
Therefore, the backbone structure of compound <bold>2</bold> was modified
in a systematic manner as reported by Yang, S. et al.<sup><xref ref-type="bibr" rid="ref53">53</xref></sup> As a result, a five-member lactam ring was found to be
more specific for the P1-site, and leucine was used at the P2-site,
which showed much better enzyme activity (>15-fold) than the other
residues (<xref rid="tbl3" ref-type="other">Table <xref rid="tbl3" ref-type="other">3</xref></xref>).
The strong binding of the five-member ring was evidenced by multiple
hydrogen-bonds in the X-ray crystal structure (PDB ID 2GX4).<sup><xref ref-type="bibr" rid="ref53">53</xref></sup> For the P2-site, replacement of phenylalanine or 4-fluorophenylalanine
with a leucine group increased the inhibitory activity of the enzyme
by 4-fold. This result indicated that the rigid and planar phenyl
ring is not favorable for binding to the S2 hydrophobic pocket (<bold>16</bold> and <bold>17</bold>). A lipophilic <italic>tert</italic>-butyl group at the P3 site further enhances the binding affinity
more than 10-fold (<bold>17</bold> and <bold>18</bold>). Furthermore,
the benzyloxy group was found to be the best replacement moiety for
P4-methylisoxazole, resulting in a more than 4-fold increment in enzyme
inhibitory activity (<bold>2</bold> and <bold>16</bold>); this group
was found to be the best group for this site. On the basis of the
docking study, this benzyloxy group has also been observed in a unique
conformation in the X-ray crystal structure (docking study of <bold>18</bold> with PDB ID 2GX4; see Supporting Information (SI), <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S1</ext-link>).<sup><xref ref-type="bibr" rid="ref53">53</xref></sup></p><table-wrap id="tbl3" position="float"><label>Table 3</label><caption><title>Peptidomimetics with a Michael Acceptor</title></caption><graphic xlink:href="jm5b01461_0038" id="fx1" position="float"></graphic><table-wrap-foot><fn id="t3fn1"><label>*</label><p><italic>K</italic><sub>i</sub>,
binding affinity; IC<sub>50</sub>, half-maximal inhibitory concentration.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec4.2"><label>4.2</label><title>Peptides
with Keto-glutamine</title><p>A novel
series of keto-glutamine analogues (<bold>19</bold>–<bold>26</bold>) with a phthalhydrazido group at the α-position were reported
as reversible inhibitors against SARS-CoV 3CL<sup>pro</sup> (<xref rid="fig9" ref-type="fig">Figure <xref rid="fig9" ref-type="fig">9</xref></xref>).<sup><xref ref-type="bibr" rid="ref54">54</xref></sup> This discovery originated due to their inhibitory activity
against the human hepatitis A virus 3C protease.<sup><xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref56">56</xref></sup> These compounds feature β and β′ functionalities
adjacent to the keto group as well as intramolecular hydrogen bonding
to the carbonyl, which makes them more electrophilic and susceptible
to hemithioacetal formation with Cys145 in the active site of the
protease. Compound <bold>25</bold> was recognized as the most potent
analogue with an inhibitory value (IC<sub>50</sub>) of 0.65 μM.
SAR studies indicated that both γ-lactam and phthalhydrazide
moieties are very important for good inhibition. Specifically, the
introduction of the γ-lactam into the inhibitor containing a
phthalhydrazide moiety greatly enhanced the inhibitory activity against
SARS-CoV 3CL<sup>pro</sup> (compare inhibitors <bold>19</bold>–<bold>22</bold> vs <bold>23</bold>–<bold>26</bold>). This was further
supported by molecular modeling studies of the active inhibitors (<bold>24</bold>–<bold>26</bold>), which show binding via an extended
β-sheet interaction with residues 163–166 of the 3CL<sup>pro</sup> and formation of hydrogen bonds between the His163 and
the P1 side chain.</p><fig id="fig9" position="float"><label>Figure 9</label><caption><p>Keto-glutamine derivatives with phthalhydrazide (<bold>19</bold>–<bold>27</bold>) and thiophene group (<bold>28</bold>).</p></caption><graphic xlink:href="jm5b01461_0010" id="gr9" position="float"></graphic></fig><p>A recent report disclosed the
X-ray crystal structure of SARS-CoV
3CL<sup>pro</sup> complexed with one of the phthalhydrazide (<bold>19</bold>)-based peptide inhibitors (<xref rid="fig10" ref-type="fig">Figure <xref rid="fig10" ref-type="fig">10</xref></xref>, PDB ID 2Z3C).<sup><xref ref-type="bibr" rid="ref57">57</xref></sup> The inhibitor
forms an unusual thiiranium ring with the nucleophilic sulfur atom
of Cys145, trapping the enzyme’s catalytic residues in configurations
similar to the intermediate states proposed to exist during the hydrolysis
of the native substrate.<sup><xref ref-type="bibr" rid="ref57">57</xref></sup> Additionally,
the data suggest that this structure resembles the proposed tetrahedral
intermediate during the deacylation step of normal peptide hydrolysis
cleavage.<sup><xref ref-type="bibr" rid="ref57">57</xref></sup> Furthermore, to prove the importance
of P1-lactam and phthalhydrazide units in inhibitor <bold>23</bold>, a series of analogues modified from P1-lactam to P1-phenyalanine
(<bold>27</bold>) or from phthalhydrazide to thiophene (<bold>28</bold>) were reported to have only weak activity against SARS-CoV 3CL<sup>pro</sup>.<sup><xref ref-type="bibr" rid="ref54">54</xref></sup></p><fig id="fig10" position="float"><label>Figure 10</label><caption><p>Crystal structure of
phthalhydrazide-based inhibitor <bold>19</bold> bound to SARS-CoV
3CL<sup>pro</sup> (PDB ID 2Z3C). The protein binding
pocket is shown in surface representation and colored in orange. The
carbon atoms of the inhibitor <bold>19</bold> and the binding pocket
residues are shown in stick model and colored in green and yellow,
respectively. The thiiranium ring formed by amino acid Cys145 is colored
in magenta.</p></caption><graphic xlink:href="jm5b01461_0011" id="gr10" position="float"></graphic></fig></sec><sec id="sec4.3"><label>4.3</label><title>Peptides
with Nitroanilide</title><p>A diverse
series of peptide anilides (<bold>29</bold>–<bold>35</bold>) were reported based on niclosamide (<xref rid="fig11" ref-type="fig">Figure <xref rid="fig11" ref-type="fig">11</xref></xref>).<sup><xref ref-type="bibr" rid="ref58">58</xref></sup> Unlike typical
nitroanilide-based peptides, which are readily hydrolyzed by serine
and cysteine protease,<sup><xref ref-type="bibr" rid="ref59">59</xref></sup> these peptides
were not efficiently cleaved by SARS-CoV 3CL<sup>pro</sup>. Niclosamide
showed no inhibitory activity at a concentration of 50 μM. The
most potent inhibitor (<bold>29</bold>) is an anilide derived from
2-chloro-4-nitro aniline, <sc>l</sc>-phenylalanine, and 4-(dimethylamino)benzoic
acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL<sup>pro</sup> with a <italic>K</italic><sub>i</sub> value of 0.03 μM
and showed high selectivity toward SARS-CoV 3CL<sup>pro</sup> (IC<sub>50</sub> = 0.06 μM) rather than other proteases such as trypsin
(IC<sub>50</sub> = 110 μM), chymotrypsin (IC<sub>50</sub> =
200 μM), and papain (IC<sub>50</sub> = 220 μM). Because
of the chlorine atom at the <italic>o</italic>-position, the 2-chloro-4-nitrophenyl
ring and amido group cannot be in a coplanar conformation, thus making
hydrolysis unfavorable.</p><fig id="fig11" position="float"><label>Figure 11</label><caption><p>Anilide-type peptidomimetics (<bold>29</bold>–<bold>35</bold>) and (2<italic>S</italic>,2<italic>S</italic>)-aza epoxide (<bold>36</bold>) and <italic>trans</italic>-aziridine
(<bold>37</bold>)
inhibitors.</p></caption><graphic xlink:href="jm5b01461_0012" id="gr11" position="float"></graphic></fig><p>Modification of compound <bold>29</bold> to a series of analogues
resulted in reduced potency (<bold>30</bold>–<bold>35</bold>).<sup><xref ref-type="bibr" rid="ref58">58</xref></sup> A docking study (<xref rid="fig12" ref-type="fig">Figure <xref rid="fig12" ref-type="fig">12</xref></xref>, PDB ID 1UK4) showed that the
2-chloro-4-nitroanilide unit of compound <bold>29</bold> occupies
the second preferred pocket. Thus, the nitro group was predicted to
be hydrogen bonded with Ala46 and His41, providing a possible key
interaction with the catalytic dyad. The (dimethylamino)phenyl group
fit into the cleft formed by Gln189–Gln192 and Met165–Pro68.<sup><xref ref-type="bibr" rid="ref58">58</xref></sup> A docking study also suggested that anilide <bold>29</bold> has the lowest binding energy (−9.1 kcal/mol) compared
to the other derivatives. This experiment supports the observations
of the enzymatic assay, which revealed the important roles of 2-chloro-4-nitroaniline
and 4-(dimethylamino)benzoic acid residues in effective inhibition.<sup><xref ref-type="bibr" rid="ref58">58</xref></sup></p><fig id="fig12" position="float"><label>Figure 12</label><caption><p>Docked pose of <bold>29</bold> (green, stick model) is
shown with
the binding pocket residues (gray, line model) and interacting residues
(orange, stick model) with SARS-CoV 3CL<sup>pro</sup> (PDB ID 1UK4). The binding pocket
of the protein is shown in surface representation and gray in color.</p></caption><graphic xlink:href="jm5b01461_0013" id="gr12" position="float"></graphic></fig></sec><sec id="sec4.4"><label>4.4</label><title>Aza-epoxide
and Aziridine Peptides</title><p>It has been reported that some novel
classes of aza-peptide epoxides
(APEs) act as inhibitors for clan CD cysteine peptidase.<sup><xref ref-type="bibr" rid="ref60">60</xref>,<xref ref-type="bibr" rid="ref61">61</xref></sup> In the compound library screening, compound <bold>36</bold> (<xref rid="fig11" ref-type="fig">Figure <xref rid="fig11" ref-type="fig">11</xref></xref>) showed prominent
activity with irreversible inhibition of SARS-CoV 3CL<sup>pro</sup> (<italic>K</italic><sub>inact</sub>/<italic>K</italic><sub>i</sub> = 1900 (±400) M<sup>–1</sup> s<sup>–1</sup>).<sup><xref ref-type="bibr" rid="ref62">62</xref></sup> From the kinetic data and crystal structure
of APEs reported by Lee T-W. et al., the 3CL<sup>pro</sup> reacts
only with the <italic>S</italic>,<italic>S</italic>-diastereomer and
not its <italic>R</italic>,<italic>R</italic>-diastereomer. In addition,
the epoxide C3 atom of APE must be in the <italic>S</italic>-configuration.</p><p>A comprehensive screening of various peptides with electrophilic
building block-attached groups (e.g., epoxides and aziridines) identified
potential 3CL<sup>pro</sup> inhibitors. The data revealed that the
aziridine- and oxirane-2-carboxylates are important for the inhibition
of 3CL<sup>pro</sup>. A trans-configured compound containing Gly-Gly-aziridine
peptide <bold>37</bold> (54% inhibition at 100 μM) was selected
as a modest active-site directed irreversible SARS-CoV 3CL<sup>pro</sup> inhibitor (<xref rid="fig11" ref-type="fig">Figure <xref rid="fig11" ref-type="fig">11</xref></xref>).<sup><xref ref-type="bibr" rid="ref63">63</xref></sup> This study also revealed that epoxide
or aziridine building blocks alone, which do not contain an amino
acid moiety, are not active.</p></sec><sec id="sec4.5"><label>4.5</label><title>Peptide Aldehydes</title><p>A series of peptide
aldehyde libraries were designed to target the SARS coronavirus, based
on the irreversible inhibitor CMK, and were shown to possess very
weak inhibitory activity against SARS protease (IC<sub>50</sub> >
500 μM).<sup><xref ref-type="bibr" rid="ref64">64</xref></sup> The inhibitor CMK binds
in a canonical mode to TGEV 3CL<sup>pro</sup> and resulted in a binding
mode with P2, P4, and P5 addressing the respective S pockets, while
P3 and P6 were exposed to the solvent (<xref rid="fig13" ref-type="fig">Figure <xref rid="fig13" ref-type="fig">13</xref></xref>A). However, in monomer A SARS-CoV 3CL<sup>pro</sup>, the CMK inhibitor follows a different side chain orientation
(noncannonical binding mode): P2, P4, and P6 residues were not positioned
to the respective pockets of the enzyme but remain solvent exposed.
Instead, P3-threonine associates with the S2 pocket, and the S4 pocket
is occupied by P5-aspargine (<xref rid="fig13" ref-type="fig">Figure <xref rid="fig13" ref-type="fig">13</xref></xref>B).</p><fig id="fig13" position="float"><label>Figure 13</label><caption><p>(A) CMK-canonical binding mode with TGEV 3CL<sup>pro</sup> (PDB
code 1P9U),<sup><xref ref-type="bibr" rid="ref43">43</xref></sup> CMK-noncanonical binding mode with active monomer
A of SARS CoV 3CL<sup>pro</sup> (PDB code 1UK4) (B),<sup><xref ref-type="bibr" rid="ref38">38</xref></sup> and
(C) the derived inhibitors <bold>38</bold> and <bold>39</bold>.</p></caption><graphic xlink:href="jm5b01461_0014" id="gr13" position="float"></graphic></fig><p>On the basis of these structural
findings, it was observed that
the sequential variations at the P sites of this initial structure
produced potent inhibitors, especially after modifications of the
P2 and P5 sites, whereas mutations of the P1 and P3 sites yielded
only moderately improved inhibitors. Peptides <bold>38</bold> (AcNSTSQ-H)
and <bold>39</bold> (AcESTLQ-H) were found to be more potent, with
the best reversible inhibitors having IC<sub>50</sub> values in the
low micromolar range (7.5 μM) (<xref rid="fig13" ref-type="fig">Figure <xref rid="fig13" ref-type="fig">13</xref></xref>C). Interestingly, these inhibitors are
assumed to bind in a noncanonical mode similar to that of CMK with
TGEV 3CL<sup>pro</sup> (<xref rid="fig13" ref-type="fig">Figure <xref rid="fig13" ref-type="fig">13</xref></xref>B). In addition, the SAR suggested that the substrate
specificity of SARS-CoV 3CL<sup>pro</sup> requires glutamine in the
P1 position and a large hydrophobic residue in the P2 position. Moreover,
X-ray crystal structures of some pentapeptide aldehydes Ac-ESTLQ-H
(<bold>40</bold>, PDB ID 3SNE), Ac-NSFSQ-H (<bold>41</bold>, PDB ID 3SNA), Ac-DSFDQ-H (<bold>42</bold>, PDB ID 3SNB), and Ac-NSTSQ-H (<bold>43</bold>, PDB ID 3SNC), complexed with
SARS-CoV 3CL<sup>pro</sup>, revealed that the S2 pocket of the enzyme
can accommodate serine and even an aspartic acid side chain in the
P2 position (see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S2</ext-link>).<sup><xref ref-type="bibr" rid="ref65">65</xref></sup> However, the cleavage efficiency of serine in
the P2-position was 160 times lower than the original substrate (P2-Leu),
and with aspartic acid, cleavage was not observed at all. Furthermore,
the same research group also determined the X-ray crystal structure
of SARS-CoV 3CL<sup>pro</sup> in complex with Cm-FF-H (<bold>44</bold>, <italic>K</italic><sub>i</sub> = 2.24 μM, see <xref rid="fig14" ref-type="fig">Figure <xref rid="fig14" ref-type="fig">14</xref></xref>A). From the complex structure
(see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S3</ext-link>, PDB ID 3SN8), compound <bold>44</bold> had a P1-phenylalanine residue located in the hydrophilic
S1 subsite resulted in hydrophobic interactions with Phe140, Leu141,
Asn142, and the P3-cinnamoyl group of Cm-FF-H. This result suggests
that the stringent specificity of SARS-CoV 3CL<sup>pro</sup> with
respect to the P1 and P2 positions can be overcome by the highly electrophilic
character of the aldehyde warhead.</p><fig id="fig14" position="float"><label>Figure 14</label><caption><p>(A) Structure of aldehydes <bold>44</bold> and <bold>45</bold> and
(B) substrate based inhibitors <bold>46</bold>–<bold>48</bold>.</p></caption><graphic xlink:href="jm5b01461_0015" id="gr14" position="float"></graphic></fig><p>A novel potent SARS-CoV 3CL<sup>pro</sup> peptide–aldehyde
inhibitor (<bold>45</bold>: <italic>K</italic><sub>i</sub> = 53 nM)
was developed as an antiviral agent against SARS-CoV and human coronavirus
HCoV 229E replication, which reduced the viral titer by 4.7 log (at
5 μM) for SARS-CoV and 5.2 log (at 1.25 μM) for HCoV 229E
(<xref rid="fig14" ref-type="fig">Figure <xref rid="fig14" ref-type="fig">14</xref></xref>A).<sup><xref ref-type="bibr" rid="ref53">53</xref></sup> This inhibitor has distinct functional groups
at the P1 to P4 sites compared to those of reference compound <bold>2</bold>. This inhibitor was designed to evaluate the issues of cell
viability, stability, and drug-like properties based on compound <bold>18</bold>. Accordingly, the leucine moiety was replaced with a bulky
cyclohexylalanine to improve the cell activity, and the ester group
was replaced with an aldehyde to avoid hydrolysis by esterase. As
a result, compound <bold>45</bold> (TG-0205221)<sup><xref ref-type="bibr" rid="ref53">53</xref></sup> displayed a very stable profile in mouse, rat, and human
plasma (<xref rid="tbl4" ref-type="other">Table <xref rid="tbl4" ref-type="other">4</xref></xref>). The
X-ray crystal structure of <bold>45</bold> (PDB ID 2GX4) revealed a unique
binding mode comprising a covalent bond, hydrogen bonds, and numerous
hydrophobic interactions (see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S4</ext-link>).<sup><xref ref-type="bibr" rid="ref53">53</xref></sup></p><table-wrap id="tbl4" position="float"><label>Table 4</label><caption><title>In Vivo Evaluation
of Compound <bold>45</bold> for Stability<xref rid="t4fn1" ref-type="table-fn">a</xref></title></caption><graphic xlink:href="jm5b01461_0039" id="fx2" position="float"></graphic><table-wrap-foot><fn id="t4fn1"><label>a</label><p>The drug was added to 90% rat, mouse,
or human plasma and incubated for 0, 30, and 120 min in respective
wells.</p></fn></table-wrap-foot></table-wrap><p>In the course of
studies on the SARS-CoV 3CL<sup>pro</sup> and
its inhibitors,<sup><xref ref-type="bibr" rid="ref66">66</xref></sup> it was found that the
mature SARS-CoV 3CL<sup>pro</sup> is very sensitive to degradation
at the Arg188/Gln189 site, which causes a loss of catalytic activity.
The stability of the SARS-CoV 3CL<sup>pro</sup> is dramatically increased
by mutating the Arg at position 188 to Ile. The enzymatic efficiency
of the R188I mutant was increased by a factor of more than 1 ×
10<sup>6</sup>. The potency of the mutant protease makes it possible
to quantitatively evaluate substrate-based peptide–aldehyde
inhibitors using conventional high-performance liquid chromatography
(HPLC). A P-site pentapeptide sequence, Ac-Ser-Ala-Val-Leu-NHCH-(CH<sub>2</sub>CH<sub>2</sub>CON(CH<sub>3</sub>)<sub>2</sub>)-CHO (<bold>46</bold>: <xref rid="fig14" ref-type="fig">Figure <xref rid="fig14" ref-type="fig">14</xref></xref>B), inhibits the catalytic activity of the SARS-CoV 3CL<sup>pro</sup> with an IC<sub>50</sub> value of 37 μM. The side chain structures,
especially at sites P1, P2, and P4, were then optimized step by step
based on X-ray crystallographic analyses of the inhibitor–protease
complex to provide potent tetra peptide aldehyde inhibitors (<bold>47</bold> and <bold>48</bold>) (<xref rid="fig14" ref-type="fig">Figure <xref rid="fig14" ref-type="fig">14</xref></xref>B).<sup><xref ref-type="bibr" rid="ref67">67</xref></sup></p></sec><sec id="sec4.6"><label>4.6</label><title>Peptides with Halomethyl Ketone or Electrophilic
Substituents</title><p>A new series of <italic>N</italic>,<italic>N</italic>′-dimethyl glutaminyl (<bold>49</bold>–<bold>53</bold>) or aspartic acid (<bold>54</bold>) inhibitors with fluoromethyl
a ketone warhead were reported as SARS-CoV 3CL<sup>pro</sup> inhibitors
(<xref rid="tbl5" ref-type="other">Table <xref rid="tbl5" ref-type="other">5</xref></xref>).<sup><xref ref-type="bibr" rid="ref68">68</xref></sup> These inhibitors were designed based on their
caspase inhibitory activities.<sup><xref ref-type="bibr" rid="ref69">69</xref>,<xref ref-type="bibr" rid="ref70">70</xref></sup> Antiviral activity
assessed by cytopathic effect (CPE) inhibition in SARS-CoV infected
Vero cultures revealed that compounds effectively inhibit both FFM1
and 6109 strains of SARS-CoV replication.</p><table-wrap id="tbl5" position="float"><label>Table 5</label><caption><title>Inhibitory
Values of Analogues <bold>49</bold>–<bold>54</bold></title></caption><graphic xlink:href="jm5b01461_0040" id="fx3" position="float"></graphic><graphic xlink:href="jm5b01461_0041" id="fx4" position="float"></graphic><table-wrap-foot><fn id="t5fn1"><label>a</label><p>Concentration of
compound inhibiting
cytopathic effect to 50% of untreated cells. Values represent the
mean (standard deviation) from three independent experiments.</p></fn><fn id="t5fn2"><label>b</label><p>Incubation of confluent CaCo2 or
Vero cell layers with different concentrations of all the dipeptides
for 3 days.</p></fn><fn id="t5fn3"><label>c</label><p>CC<sub>50</sub>, 50% cytotoxic concentration.</p></fn></table-wrap-foot></table-wrap><p>Among these inhibitors, compound <bold>49</bold> exhibited promising
activity with low toxicity in cells, protecting the cells with an
EC<sub>50</sub> value of 2.5 μM and exhibiting a selectivity
index >40.<sup><xref ref-type="bibr" rid="ref68">68</xref></sup> In addition, compound <bold>49</bold> showed low toxicity in mice. From the SAR studies, P1-glutamine,
a residue that has been identified as a conservative recognition site
in SARS-CoV 3CL<sup>pro</sup>, can be replaced by <italic>N</italic>,<italic>N</italic>′-dimethyl glutamine (see <bold>49</bold>–<bold>51</bold>). However, compound <bold>54</bold>, a potent
caspase inhibitor with P1-aspartic acid, abolished activity in this
series.<sup><xref ref-type="bibr" rid="ref68">68</xref></sup> Furthermore, the P2-leucine can
also be replaced by isoleucine (<bold>50</bold>) and valine (<bold>51</bold>). The active compounds <bold>49</bold>–<bold>51</bold> were found to be inactive against rhinovirus type-2 in a cell-based
assay suggested that compounds <bold>49</bold>–<bold>51</bold> are specific against SARS-CoV. Compound <bold>51</bold> was found
to have low toxicity in mice after administration of a single dose
at 25, 50, and 100 mg/kg. No weight loss or behavioral changes nor
any gross pathology of the major organs was observed at the tested
doses. This study suggested that compound <bold>51</bold> could be
a promising candidate for animal efficacy studies<sup><xref ref-type="bibr" rid="ref68">68</xref></sup></p><p>Abeles et al. proposed that trifluoromethyl ketones
(FMK)<sup><xref ref-type="bibr" rid="ref71">71</xref></sup> can also be used as protease inhibitors.<sup><xref ref-type="bibr" rid="ref72">72</xref></sup> An interesting feature of these inhibitors is
the formation of thermodynamically stable hemiketal or hemithioketal
that occurs upon nucleophilic attack by the Ser-hydroxyl or Cys-thiol
groups present in the serine or cysteine protease, respectively. On
the basis of this observation, Hayashi et al. reported Gln-derived
CF<sub>3</sub><sup>–</sup> ketones <bold>55</bold> and <bold>56</bold> as SARS-CoV 3CL<sup>pro</sup> inhibitors (<xref rid="fig15" ref-type="fig">Figure <xref rid="fig15" ref-type="fig">15</xref></xref>).<sup><xref ref-type="bibr" rid="ref73">73</xref></sup> Compounds <bold>55</bold> and <bold>56</bold> showed modest inhibitory
activity due to the formation of typical cyclic structures that are
not expected to interact effectively with the active site.<sup><xref ref-type="bibr" rid="ref69">69</xref></sup> To avoid this problem, the side chain at the
P1 site was modified in order to block cyclization.<sup><xref ref-type="bibr" rid="ref74">74</xref>−<xref ref-type="bibr" rid="ref77">77</xref></sup> As shown in <xref rid="fig15" ref-type="fig">Figure <xref rid="fig15" ref-type="fig">15</xref></xref>, compounds <bold>57</bold>(<xref ref-type="bibr" rid="ref74">74</xref>) and <bold>58</bold>(<xref ref-type="bibr" rid="ref75">75</xref>) showed excellent activities and further optimization provided
compounds <bold>59</bold>–<bold>60</bold>,<sup><xref ref-type="bibr" rid="ref76">76</xref>,<xref ref-type="bibr" rid="ref77">77</xref></sup> which showed low nanomolar inhibition of SARS-CoV 3CL<sup>pro</sup>.</p><fig id="fig15" position="float"><label>Figure 15</label><caption><p>Inhibitors with halomethyl ketones and their derivatives <bold>55</bold>–<bold>60</bold>.</p></caption><graphic xlink:href="jm5b01461_0016" id="gr15" position="float"></graphic></fig><p>While continuing to explore the SARs based on FMK inhibitors,
a
series of trifluoro methyl ketones <bold>61</bold>–<bold>68</bold> were developed, mainly focusing on the P1 and P2–P4 positions
(<xref rid="tbl6" ref-type="other">Table <xref rid="tbl6" ref-type="other">6</xref></xref>).<sup><xref ref-type="bibr" rid="ref78">78</xref></sup> Three different amino acids were demonstrated
as variable residues at positions P1–P4. The inhibitory activities
were observed to range from 10 to 50 μM. The potent inhibitor,
compound <bold>61</bold>, which possesses the same moiety as the substrate
sequence of the peptide at the P1–P4 sites, exhibited comparable
activity to other compounds. As shown in <xref rid="tbl6" ref-type="other">Table <xref rid="tbl6" ref-type="other">6</xref></xref>, replacement of the P1-benzyl (<bold>62</bold>) with a methyl group (<bold>64</bold>) or hydrogen (<bold>66</bold>) resulted in a loss of activity. Inhibitor <bold>61</bold> showed
time-dependent inhibition, with a <italic>K</italic><sub>i</sub> value
of 0.3 μM after a 4 h incubation.<sup><xref ref-type="bibr" rid="ref78">78</xref></sup></p><table-wrap id="tbl6" position="float"><label>Table 6</label><caption><title>Inhibitory Activity of Halomethyl
Ketones<xref rid="t6fn1" ref-type="table-fn">a</xref></title></caption><graphic xlink:href="jm5b01461_0042" id="fx5" position="float"></graphic><table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="char" char="."></col></colgroup><thead><tr><th style="border:none;" align="center">compd</th><th style="border:none;" align="center">R</th><th style="border:none;" align="center">X</th><th style="border:none;" align="center" char=".">IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td style="border:none;" align="left"><bold>61</bold></td><td style="border:none;" align="left">see above structure</td><td style="border:none;" align="left">see above structure</td><td style="border:none;" align="char" char=".">10</td></tr><tr><td style="border:none;" align="left"><bold>62</bold></td><td style="border:none;" align="left">Bn</td><td style="border:none;" align="left">Cbz-Leu</td><td style="border:none;" align="char" char=".">15</td></tr><tr><td style="border:none;" align="left"><bold>63</bold></td><td style="border:none;" align="left">Bn</td><td style="border:none;" align="left">Cbz-Phe</td><td style="border:none;" align="char" char=".">20</td></tr><tr><td style="border:none;" align="left"><bold>64</bold></td><td style="border:none;" align="left">Me</td><td style="border:none;" align="left">Boc-Leu</td><td style="border:none;" align="char" char=".">40</td></tr><tr><td style="border:none;" align="left"><bold>65</bold></td><td style="border:none;" align="left">H</td><td style="border:none;" align="left">Boc-γ-Glu(OtBu)-Ala</td><td style="border:none;" align="char" char=".">40</td></tr><tr><td style="border:none;" align="left"><bold>66</bold></td><td style="border:none;" align="left">H</td><td style="border:none;" align="left">γ-Glu-Ala</td><td style="border:none;" align="char" char=".">50</td></tr><tr><td style="border:none;" align="left"><bold>67</bold></td><td style="border:none;" align="left">Bn</td><td style="border:none;" align="left">CH<sub>3</sub>(CH<sub>2</sub>)<sub>8</sub>CO-Leu</td><td style="border:none;" align="char" char=".">50</td></tr><tr><td style="border:none;" align="left"><bold>68</bold></td><td style="border:none;" align="left">Bn</td><td style="border:none;" align="left">CH<sub>3</sub>(CH<sub>2</sub>)<sub>7</sub>CO-Leu</td><td style="border:none;" align="char" char="."> >50</td></tr></tbody></table><table-wrap-foot><fn id="t6fn1"><label>a</label><p>IC<sub>50</sub>, half-maximal inhibitory
concentration; Bn, benzyl; Me, methyl.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec4.7"><label>4.7</label><title>Symmetric Peptides</title><p>It was previously
proposed that HIV protease inhibitors could serve as good starting
points for the development of SARS-CoV 3CL<sup>pro</sup> inhibitors.
In general, reversible inhibitors produce fewer side effects than
suicide inhibitors and are thus more suitable for drug development.
Recently, compound <bold>69</bold>, a noncovalent HIV protease inhibitor
(<italic>K</italic><sub>i</sub> = 1.5 nM), was used as a lead structure
and optimized using computational analysis for the development of
SARS-CoV 3CL<sup>pro</sup> inhibitors.<sup><xref ref-type="bibr" rid="ref79">79</xref></sup> As shown in the <xref rid="fig16" ref-type="fig">Figure <xref rid="fig16" ref-type="fig">16</xref></xref>, introduction of peripheral Val-Ala residues in place of
the Cbz groups or introduction of 3-indolyl groups in place of the
phenyl groups in compound <bold>69</bold> led to the formation of
inhibitors (<bold>70</bold> and <bold>71</bold>) that were potent
SARS-CoV 3CL<sup>pro</sup> inhibitors with <italic>K</italic><sub>i</sub> values of 0.34 and 0.073 μM, respectively. In addition,
compound <bold>71</bold> is highly selective for the 3CL<sup>pro</sup>, with no inhibition observed against HIV protease at 100 μM.</p><fig id="fig16" position="float"><label>Figure 16</label><caption><p>Symmetric
peptide diols <bold>69</bold>–<bold>71</bold>.</p></caption><graphic xlink:href="jm5b01461_0017" id="gr16" position="float"></graphic></fig></sec></sec><sec id="sec5"><label>5</label><title>Small Molecule Inhibitors
of SARS-CoV 3CL<sup>pro</sup></title><p>The other category of inhibitors against SARS-CoV 3CL<sup>pro</sup> includes nonpeptidic small molecules. In general, small molecules
have been found to be noncovalent or reversible covalent inhibitors,
which have advantages regarding side effects and toxicity which often
arise with covalent inhibitors. These inhibitors were discovered by
high throughput screening of synthetic compounds and natural products.</p><sec id="sec5.1"><label>5.1</label><title>Etacrynic Acid Derivatives</title><p>An HPLC-based
screen of electrophilic compounds revealed etacrynic acid derivatives <bold>73</bold> (75% inhibition at 100 μM and <italic>K</italic><sub>i</sub> = 45.8 μM) and <bold>74</bold> (88% inhibition at 100
μM and <italic>K</italic><sub>i</sub> = 35.3 μM) as effective
inhibitors of SARS-CoV 3CL<sup>pro</sup>.<sup><xref ref-type="bibr" rid="ref80">80</xref></sup> These inhibitors were obtained from the sequential modifications
of an etacrynic acid (<bold>72</bold>), a well-known diuretic drug,<sup><xref ref-type="bibr" rid="ref81">81</xref></sup> and also showed activity toward the cysteine
proteases such as papain protease (<italic>K</italic><sub>i</sub> =
375 μM).<sup><xref ref-type="bibr" rid="ref82">82</xref></sup> Ester <bold>73</bold> showed
more potency toward papain protease (<italic>K</italic><sub>i</sub> = 3.2 μM) than SARS-CoV 3CL<sup>pro</sup> (<italic>K</italic><sub>i</sub> = 45.8 μM). However, etacrynic acid amide (<bold>74</bold>, <italic>K</italic><sub>i</sub> = 35.3 μM) was found
to have more affinity toward SARS-CoV 3CL<sup>pro</sup>. The SAR studies
revealed that chloro substituents on the phenyl moiety were necessary
for SARS-CoV 3CL<sup>pro</sup> inhibition (<xref rid="fig17" ref-type="fig">Figure <xref rid="fig17" ref-type="fig">17</xref></xref>). Compounds with an unsubstituted phenyl
ring or methyl substituent were inactive at 100 μM.<sup><xref ref-type="bibr" rid="ref80">80</xref></sup> In addition, it is quite promising that only
esters or amides display 3CL<sup>pro</sup> inhibition.<sup><xref ref-type="bibr" rid="ref80">80</xref></sup></p><fig id="fig17" position="float"><label>Figure 17</label><caption><p>Structural features of etacrynic acids produce their inhibitory
activity against SARS-CoV 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0018" id="gr17" position="float"></graphic></fig></sec><sec id="sec5.2"><label>5.2</label><title>Isatin (2,3-Dioxindole) Inhibitors</title><p>It has been established that certain isatin (2,3-dioxindole) compounds
are potent inhibitors of rhinovirus 3C<sup>pro</sup>.<sup><xref ref-type="bibr" rid="ref83">83</xref></sup> Because the proteases of SARS-CoV and rhinovirus share
similar active sites and catalytic residues,<sup><xref ref-type="bibr" rid="ref15">15</xref></sup> isatin derivatives may also be good candidates for anti-SARS drug
development. Accordingly, a series of synthetic isatin derivatives
(<bold>75</bold>–<bold>81</bold>) were reported as noncovalent
SARS protease inhibitors,<sup><xref ref-type="bibr" rid="ref84">84</xref>,<xref ref-type="bibr" rid="ref85">85</xref></sup> unlike rhinovirus 3C<sup>pro</sup>, which has a covalent bond binding mode (<xref rid="tbl7" ref-type="other">Table <xref rid="tbl7" ref-type="other">7</xref></xref>). These isatin derivatives
inhibited SARS-CoV 3CL<sup>pro</sup> in the low micromolar range,
and inhibitors <bold>78</bold> and <bold>80</bold> were found to be
the most potent. SAR studies revealed that the inhibitory potency
heavily depended on the hydrophobicity and electron affinity of the
substituents on the isatin core. Moreover, computational analysis
(docking studies of <bold>78</bold> with PDB ID 1UK4, see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S5</ext-link>) of both active compounds showed that
they fit very well into the active pocket of SARS-CoV 3CL<sup>pro</sup>. The two carbonyl groups on isatin could form hydrogen bond interactions
with the NH groups on Gly143, Ser144, Cys145, and the His41 side chain.
In addition, compounds <bold>78</bold> and <bold>80</bold>(<xref ref-type="bibr" rid="ref86">86</xref>) exhibited better selectivity for SARS than for
other proteases including papain (103, 87.24 μM), chymotrypsin
(1 mM, 10.4 μM) and trypsin (362, 243 μM).</p><table-wrap id="tbl7" position="float"><label>Table 7</label><caption><title>Inhibitory Activities of Isatin Derivatives</title></caption><graphic xlink:href="jm5b01461_0043" id="fx6" position="float"></graphic><graphic xlink:href="jm5b01461_0044" id="fx7" position="float"></graphic></table-wrap></sec><sec id="sec5.3"><label>5.3</label><title>Flavonoid
and Biflavonoid Derivatives</title><p>Chemotherapeutic agents that
target viral entry are an important
class of antiviral therapy as they can block the propagation of the
virus at an early stage, thus minimizing the chance for the virus
to evolve and acquire drug resistance. Screening of Chinese herbal
medicine-based molecules resulted in the discovery of luteolin (<bold>82</bold>) as inhibitor of wild-type SARS-CoV activity with an effective
concentration (EC<sub>50</sub>) of 10.6 μM (<xref rid="fig18" ref-type="fig">Figure <xref rid="fig18" ref-type="fig">18</xref></xref>).<sup><xref ref-type="bibr" rid="ref87">87</xref></sup> Compound <bold>82</bold> was identified as active using a two-step
screening method consisting of frontal affinity chromatography–mass
spectrometry coupled with a viral infection assay based on a human
immunodeficiency virus (HIV)-luc/SARS pseudotyped virus. This flavone
analogue binds with the surface spike protein of SARS-CoV and thus
can interfere with the entry of the virus into the host cells. However,
the related flavone quercetin (<bold>83</bold>) and its derivatives
exhibited modest inhibitory activity against the SARS virus (<xref rid="fig18" ref-type="fig">Figure <xref rid="fig18" ref-type="fig">18</xref></xref>).</p><fig id="fig18" position="float"><label>Figure 18</label><caption><p>Flavonoids and biflavonoid
derivatives.</p></caption><graphic xlink:href="jm5b01461_0019" id="gr18" position="float"></graphic></fig><p>Quercetin-3-β-galactoside
(<bold>84</bold>) was identified
as a potential inhibitor of SARS-CoV and showed inhibitory activity
with an IC<sub>50</sub> of 42.79 ± 4.97 μM in a SPR/FRET-based
enzymatic inhibition assay.<sup><xref ref-type="bibr" rid="ref88">88</xref></sup> The docking
study of <bold>84</bold> with SARS-CoV 3CL<sup>pro</sup> suggested
that the residue Gln189 (Q189) plays a key role in the binding interaction.
To confirm this prediction, the binding mode of <bold>84</bold> was
compared between the wild-type SARS-CoV 3CL<sup>pro</sup> and its
mutated SARS-CoV 3CL<sup>pro</sup> Q189A. This comparative study was
consistent with the docking prediction and the inhibitory potency
of <bold>84</bold> on SARS-CoV 3CL<sup>pro</sup> Q189A was significantly
decreased to 127.89 ± 10.06 μM. Besides, the experimental
evidence showed that the enzymatic activity of SARS-CoV 3CL<sup>pro</sup> was not affected by the Q189A mutation. The <sc>l</sc>-fucose derivative
(<bold>85</bold>) exhibited 2-fold potent inhibitory activity compared
to <bold>84</bold>. The SAR and molecular docking studies of these
new derivatives revealed that four hydroxy groups on the quercetin
moiety are key determinants for its potential biological activity.</p><p>As part of ongoing investigation of bioflavonoids from medicinal
plants as potential SARS-CoV 3CL<sup>pro</sup> inhibitors, a series
of inhibitors (<bold>86</bold>–<bold>90</bold>) were reported
from the leaves of <italic>Torreya nucifera</italic> (<xref rid="fig18" ref-type="fig">Figure <xref rid="fig18" ref-type="fig">18</xref></xref>).<sup><xref ref-type="bibr" rid="ref89">89</xref></sup> Among the isolated compounds, biflavone amentoflavone
(<bold>86</bold>) was recognized as a potent noncompetitive inhibitor,
exhibiting an IC<sub>50</sub> value of 8.3 μM. An SAR study
demonstrated the three authentic flavones, apigenin (<bold>90</bold>), luteolin (<bold>82</bold>), and quercetin (<bold>83</bold>), showed
inhibitory activities (IC<sub>50</sub>) of 280.8, 20.2, and 23.8 μM,
respectively. The activity of amentoflavone (<bold>86</bold>) was
consistent with the binding interactions (docking studies of <bold>86</bold> with PDB ID 2Z3E, see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S6</ext-link>), with
Val186 and Gln192 as one of the key binding modes with the target
site. Moreover, the binding energy difference between apigenin (<bold>90</bold>; −7.79 kcal/mol) and amentoflavone (<bold>86</bold>; −11.42 kcal/mol) are consistent with a 30-fold lower IC<sub>50</sub> value of <bold>86</bold> toward SARS-CoV 3CL<sup>pro</sup> than apigenin (<bold>90</bold>).</p></sec><sec id="sec5.4"><label>5.4</label><title>Terpenoid
Derivatives</title><p>A series of
diterpenoids (<bold>91</bold>–<bold>93</bold>) from <italic>Torreya nucifera</italic> were evaluated for their anti-SARS
activity (<xref rid="fig19" ref-type="fig">Figure <xref rid="fig19" ref-type="fig">19</xref></xref>).<sup><xref ref-type="bibr" rid="ref89">89</xref></sup> However, these terpenoids exhibited
very low activity compared to biflavonoids against SARS-CoV 3CL<sup>pro</sup> at concentrations up to 100 μM. One exception was
ferruginol (<bold>91</bold>, IC<sub>50</sub> = 49.6 μM), which
exhibited significantly greater activity. Moreover, the quinone-methide
triterpenoids celastrol (<bold>94</bold>), pritimererin (<bold>95</bold>), tingenone (<bold>96</bold>), and iguesterin (<bold>97</bold>)
were isolated from the methanol (95%) extracts of <italic>Tripterygium
regelii</italic> (Celastraceae) and showed moderate inhibitory
activities with IC<sub>50</sub> values of 2.6, 9.9, 5.5, and 10.3
μM, respectively, whereas the corresponding a semisynthetic
analogue dihydrocelastrol (<bold>98</bold>: IC<sub>50</sub> = 21.7
μM) reduced the inhibitory potency (<xref rid="fig19" ref-type="fig">Figure <xref rid="fig19" ref-type="fig">19</xref></xref>).<sup><xref ref-type="bibr" rid="ref90">90</xref></sup> A SAR study
suggested that the quinone–methide moiety in the A ring and
the more hydrophobic E-ring assist in producing the potent inhibitory
activity. The compounds mentioned above (<bold>91</bold>–<bold>98</bold>) have been proven to be competitive inhibitors using kinetic
analysis.</p><fig id="fig19" position="float"><label>Figure 19</label><caption><p>Terpenoid derivatives with inhibitory activity against SARS-CoV
3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0020" id="gr19" position="float"></graphic></fig><p>Furthermore, abietane-type
diterpenoids and lignoids exhibit a
strong anti-SARS-CoV effect.<sup><xref ref-type="bibr" rid="ref91">91</xref></sup> In particular,
betulinic acid <bold>99</bold> and savinin <bold>100</bold> were shown
to act as competitive inhibitors against SARS-CoV 3CL<sup>pro</sup> with the <italic>K</italic><sub>i</sub> values of 8.2 and 9.1 μM,
respectively (<xref rid="fig19" ref-type="fig">Figure <xref rid="fig19" ref-type="fig">19</xref></xref>).<sup><xref ref-type="bibr" rid="ref91">91</xref></sup> On the basis of molecular modeling
analysis, it was observed that the competitive inhibition of <bold>99</bold> and <bold>100</bold> on SARS-CoV 3CL<sup>pro</sup> activity
was consistent with the formation of multiple hydrogen bond interactions
between the compound and specific amino acid residues located at the
active site of the pocket of the protease enzyme.</p></sec><sec id="sec5.5"><label>5.5</label><title>Sulfone, Dihydroimidazole, and <italic>N</italic>-Phenyl-2-(2-pyrimidinylthio)acetamide
Type Analogues</title><p>Structure-based
virtual screening of a chemical database containing 58855 compounds
for SARS-CoV 3CL<sup>pro</sup> inhibition produced two hits, sulfone
(<bold>101</bold>) and dihydroimidazole (<bold>102</bold>) (<xref rid="fig20" ref-type="fig">Figure <xref rid="fig20" ref-type="fig">20</xref></xref>).<sup><xref ref-type="bibr" rid="ref92">92</xref></sup> The core structures of these two hits, defined by a molecular
docking study, were used for further searches of analogues.</p><fig id="fig20" position="float"><label>Figure 20</label><caption><p>Sulfone,
dihydroimidazole, and <italic>N</italic>-phenyl-2-(2-pyrimidinylthio)acetamide-type
analogues.</p></caption><graphic xlink:href="jm5b01461_0021" id="gr20" position="float"></graphic></fig><p>Accordingly, 21 analogues
derived from these two hits exhibited
IC<sub>50</sub> values below 50 μM, and the two most potent
compounds (<bold>103</bold> and <bold>104</bold>) obtained from each
hit show IC<sub>50</sub> values of 0.3 and 3 μM, respectively.<sup><xref ref-type="bibr" rid="ref92">92</xref></sup> Furthermore, a combination of structure-based
virtual screening and three-dimensional quantitative structure–activity
relationship (3D-QSAR) studies of compound databases of 59363 compounds
led to the identification of compounds <bold>105</bold>–<bold>110</bold>, which exhibited modest inhibition with IC<sub>50</sub> values of 3, 10, 11, 12, 14, and 15 μM, respectively (<xref rid="fig20" ref-type="fig">Figure <xref rid="fig20" ref-type="fig">20</xref></xref>).<sup><xref ref-type="bibr" rid="ref93">93</xref></sup> On the basis of the structure–functional analysis,
a common core structure, <italic>N</italic>-phenyl-2-(2-pyrimidinylthio)acetamide,
was identified. A potential binding mode of compound <bold>105</bold> was predicted by the molecular modeling study (docking study of <bold>107</bold> with PDB ID 1UK4, see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S7</ext-link>); the
strong interaction of benzene and thiazole units with Glu166, Leu167,
Pro168, and Gln192 at the SARS-CoV 3CL<sup>pro</sup> active site could
explain its increase in potency.</p></sec><sec id="sec5.6"><label>5.6</label><title>Active
Heterocyclic Ester Analogues</title><p>Wong and co-workers<sup><xref ref-type="bibr" rid="ref94">94</xref></sup> reported a novel
class of mechanism-based irreversible inhibitors with activity in
the nanomolar range, using combinatorial synthesis in microtiter plates
followed by in situ screening.<sup><xref ref-type="bibr" rid="ref95">95</xref>−<xref ref-type="bibr" rid="ref97">97</xref></sup> Instead of the expected amide
reaction products, a series of benzotriazole esters (<bold>111</bold>–<bold>114</bold>) were isolated. Surprisingly, the inhibitory
activity of these analogues was much higher than that of the other
small molecules or peptidomimetics. Further SAR optimization yielded
analogues <bold>115</bold>–<bold>118</bold> with nanomolar
inhibitory activities (<xref rid="fig21" ref-type="fig">Figure <xref rid="fig21" ref-type="fig">21</xref></xref>). An interesting point was found that the esters derived
from the benzoic acid-containing electron withdrawing substituents,
e.g., NO<sub>2</sub>, CN and CF<sub>3</sub> were susceptible to hydrolysis,
whereas esters <bold>111</bold>–<bold>114</bold> and those
with electron-donating substituents were relatively stable in pH 5.0–8.0
solutions over 24 h at room temperature. Compound <bold>116</bold> (<italic>K</italic><sub>i</sub> = 7.5 nM) was the most potent among
the benzotriazole esters.<sup><xref ref-type="bibr" rid="ref94">94</xref></sup> The possible
mode of action could be acylation of Cys145 at the active site assisted
by the catalytic dyad; this irreversible enzyme acylation was verified
by electrospray ionization mass spectrometry of the inhibited enzyme
with the compound <bold>112</bold> (<xref rid="fig22" ref-type="fig">Figure <xref rid="fig22" ref-type="fig">22</xref></xref>).</p><fig id="fig21" position="float"><label>Figure 21</label><caption><p>Active heterocyclic ester analogues and their
inhibitory activities
against SARS-CoV 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0022" id="gr21" position="float"></graphic></fig><fig id="fig22" position="float"><label>Figure 22</label><caption><p>Mechanism of covalent bond formation of inhibitors <bold>112</bold> and <bold>120</bold> with the active site cysteine residue of SARS-CoV
3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0023" id="gr22" position="float"></graphic></fig><p>In addition, the recent
X-ray crystal structure of the SARS-CoV
3CL<sup>pro</sup> complex with the benzotriazole ester also confirmed
that the active-site cysteine is acylated by the ester ligand which
acts as a suicide inhibitor.<sup><xref ref-type="bibr" rid="ref98">98</xref></sup> It should
be noted that the formation of <italic>N</italic>-hydroxybenzotriazole
is a very potent inhibitor of CYP450 enzymes. Heteroaromatic ester <bold>119</bold> (IC<sub>50</sub> = 0.5 μM) was also identified as
a potent inhibitor of the SARS coronavirus.<sup><xref ref-type="bibr" rid="ref99">99</xref></sup> The 5-chloropyridine moiety in compound <bold>119</bold> proved
to be the key unit for activity against SARS-CoV 3CL<sup>pro</sup>. Continuing SAR studies provided the very potent inhibitors <bold>120</bold>–<bold>123</bold>, with inhibitory activities spanning
from the micromolar to nanomolar range.</p><p>The structural biology
analysis suggested, in addition to the halopyridyl
unit, the other aromatic rings are also key factors for potent inhibition
(<xref rid="fig21" ref-type="fig">Figure <xref rid="fig21" ref-type="fig">21</xref></xref>).<sup><xref ref-type="bibr" rid="ref100">100</xref>,<xref ref-type="bibr" rid="ref101">101</xref></sup> A covalent bond formation mechanism for the enzyme–inhibitor
complex (<bold>120</bold>) has been proposed on the basis of electrospray
mass spectrometry investigation (<xref rid="fig22" ref-type="fig">Figure <xref rid="fig22" ref-type="fig">22</xref></xref>).</p><p>However, another strategy was demonstrated
by combining key parts
of the previously mentioned mechanism-based inhibitors (<bold>116</bold> and <bold>119</bold>) to produce a novel series of 5-chloropyridinyl
indolecarboxylate inhibitors (<bold>124</bold>–<bold>128</bold>) with enzymatic potency in the submicromolar range (<xref rid="fig23" ref-type="fig">Figure <xref rid="fig23" ref-type="fig">23</xref></xref>).<sup><xref ref-type="bibr" rid="ref102">102</xref></sup> The SAR study suggested that the positions of the carboxylic acid
ester and free indole hydrogen (NH) are critical for activity. Indole
carboxylate <bold>124</bold> with carboxylate functionality at position
4 was the most potent inhibitor with an enzyme inhibitory activity
(IC<sub>50</sub>) of 30 nM and an antiviral EC<sub>50</sub> value
of 6.9 μM.</p><fig id="fig23" position="float"><label>Figure 23</label><caption><p>Active 5-chloropyridine ester analogues and their inhibitory
activity
against SARS 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0024" id="gr23" position="float"></graphic></fig></sec><sec id="sec5.7"><label>5.7</label><title>Aryl Methylene Ketones and Fluoro Methylene
Ketones</title><p>5-Halopyridinyl-3-aromatic esters, as described in
a previous <xref rid="sec5.6" ref-type="other">section <xref rid="sec5.6" ref-type="other">5.6</xref></xref>, act as highly potent inhibitors of SARS-CoV 3CL<sup>pro</sup> with
IC<sub>50</sub> values in the low nanomolar range. They initially
bind competitively and strongly to the active site but are then hydrolyzed
by the enzyme as substrates and released. Despite their potent inhibition
of SARS-CoV 3CL<sup>pro</sup> and relatively long half-life in buffer
at neutral pH values, they are likely to be problematic as drug candidates
due to their propensity to be rapidly hydrolyzed by lipase, esterase,
and other enzyme in the mammalian cells. Moreover, these compounds
can also potentially react nonspecifically with other thiols or nucleophiles
in mammalian cells, thereby leading to toxicity. Therefore, to develop
stable and noncovalent inhibitors based on pyridinyl esters, a group
of methylene ketones and corresponding mono and difluorinated methylene
ketones were reported as SARS-CoV 3CL<sup>pro</sup> inhibitors by
Zhang. J. et al. (<xref rid="fig24" ref-type="fig">Figure <xref rid="fig24" ref-type="fig">24</xref></xref>).<sup><xref ref-type="bibr" rid="ref103">103</xref></sup> Compounds <bold>129</bold>, <bold>131</bold>, and <bold>132</bold> showed the best inhibition,
and specifically, inhibitor <bold>129</bold> was the most potent among
these analogues. The molecular modeling study of these active ketone
analogues predicts a binding conformation similar to that of corresponding
pyridinyl esters.<sup><xref ref-type="bibr" rid="ref100">100</xref>,<xref ref-type="bibr" rid="ref101">101</xref></sup> A SAR study suggested that fluorination
decreases inhibition despite enhancing the electrophilicity of the
carbonyl carbon. Enzymatic analysis and ESI-MS studies indicate that
these inhibitors utilize a noncovalent, reversible mechanism of action.</p><fig id="fig24" position="float"><label>Figure 24</label><caption><p>Halomethyl
pyridyl ketones and their inhibition potential against
SARS-CoV 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0025" id="gr24" position="float"></graphic></fig></sec><sec id="sec5.8"><label>5.8</label><title>Pyrazolone and Pyrimidines</title><p>High throughput
screening identified 3,3-dihydropyrazolidine <bold>133</bold>(<xref ref-type="bibr" rid="ref104">104</xref>) and tetrasubstituted pyrazole <bold>134</bold>,<sup><xref ref-type="bibr" rid="ref105">105</xref></sup> which displayed 1,3,5-triaryl substitution
patterns, as SARS-CoV 3CL<sup>pro</sup> inhibitors. Further exploration
of SAR produced a series of pyrazolones that demonstrated inhibitory
activities against SARS-CoV 3CL<sup>pro</sup> (<xref rid="fig25" ref-type="fig">Figure <xref rid="fig25" ref-type="fig">25</xref></xref>).<sup><xref ref-type="bibr" rid="ref106">106</xref></sup> Among them,
compounds <bold>135</bold>–<bold>137</bold> exhibited potent
inhibitory activities with the IC<sub>50</sub> values of 5.5, 6.8,
and 8.4 μM, respectively.</p><fig id="fig25" position="float"><label>Figure 25</label><caption><p>Pyrazolones and pyrimidines and their
inhibition potential against
SARS-CoV 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0026" id="gr25" position="float"></graphic></fig><p>Structure–functionality analysis indicated that the
4-carboxylbenzylidine-aryl
ring attached to C4-of pyrazolone accompanied by electron withdrawing
groups, such as CN, NO<sub>2</sub>, and F, favors inhibitory activity.
Molecular modeling studies of the active compound <bold>137</bold> predicted that the <italic>N</italic>1-phenyl group located in the
S1 pocket and the carboxyl benzylidene group in the S3 pocket of 3CL<sup>pro</sup> is crucial for its inhibitory activity. Pyrimidine derivatives
(<bold>138</bold>–<bold>140</bold>) were designed, and their
anti-SARS activity was reported (<xref rid="fig25" ref-type="fig">Figure <xref rid="fig25" ref-type="fig">25</xref></xref>).<sup><xref ref-type="bibr" rid="ref107">107</xref>,<xref ref-type="bibr" rid="ref108">108</xref></sup> Compound <bold>140</bold> was the most potent inhibitor that showed enzyme inhibitory activity
(IC<sub>50</sub> = 6.1 μM) against SARS-CoV 3CL<sup>pro</sup>. SAR studies revealed that the presence of nitro functionality at
position 4 on the benzylidene ring was more important for activity
enhancement. This potent activity was consistent with a molecular
docking study (docking study of <bold>140</bold> with PDB ID 1UK4, see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Figure S8</ext-link>);<sup><xref ref-type="bibr" rid="ref38">38</xref></sup> the
oxygen of the nitro group formed a hydrogen bond with side chains
of Gly143 and Cys145. In addition, the 4-chloro phenyl ring was predicted
to fit into the S2 pocket due to hydrophobic inter actions.</p></sec><sec id="sec5.9"><label>5.9</label><title>Decahydroisoquinoline Derivatives</title><p>Starting from the
peptide inhibitor <bold>47</bold> (see <xref rid="sec4.5" ref-type="other">section <xref rid="sec4.5" ref-type="other">4.5</xref></xref>),<sup><xref ref-type="bibr" rid="ref67">67</xref></sup> a novel
nonpeptide decahydroisoquinoline inhibitor
was designed and synthesized based on the cleavage site interactions
at the S1, and hydrophobic interaction at the S2 sites of SARS SARS-CoV
3CL<sup>pro</sup>.<sup><xref ref-type="bibr" rid="ref109">109</xref></sup> The decahydroisoquinoline
inhibitors (<bold>141</bold>–<bold>144</bold>, <xref rid="fig26" ref-type="fig">Figure <xref rid="fig26" ref-type="fig">26</xref></xref>) showed weak inhibitory activities
for SARS-CoV 3CL<sup>pro</sup>, which confirmed that the fused ring
structure of the decahydroisoquinolin scaffold can be accommodated
in the active site of SARS-CoV 3CL<sup>pro</sup>. From the X-ray crystallographic
studies (PDB ID 4TWW), it was confirmed that the decahydroisoquinoline inhibitors were
at the active site cleft of 3CL<sup>pro</sup>, as observed in peptide–aldehyde
inhibitors. The decahydroisoquinoline scaffold was inserted into a
large S2 pocket and occupied most of the pocket. The P1 site imidazole
was inserted into the S1 pocket as expected. These interactions were
effective in holding the terminal aldehyde tightly inside the active
site cleft, which resulted in the compact fitting of the novel scaffold
to SARS-CoV 3CL<sup>pro</sup>.</p><fig id="fig26" position="float"><label>Figure 26</label><caption><p>Novel decahydroisoquinoline derivatives
as SARS-CoV 3CL<sup>pro</sup> inhibitors.</p></caption><graphic xlink:href="jm5b01461_0027" id="gr26" position="float"></graphic></fig></sec><sec id="sec5.10"><label>5.10</label><title>3-Pyridyl and Benzotriazole-Based SARS-CoV
3CL<sup>pro</sup> Inhibitors</title><p>Jacobs et al. conducted a high-throughput
screening of NIH molecular libraries (∼293000 compounds) by
evaluating the inhibition of 3CL<sup>pro</sup> mediated peptide cleavage
using a novel FRET-based substrate.<sup><xref ref-type="bibr" rid="ref110">110</xref>,<xref ref-type="bibr" rid="ref111">111</xref></sup> In this screen,
a dipeptide class, represented by 3-pyridyl-based hit <bold>145</bold> (<xref rid="fig27" ref-type="fig">Figure <xref rid="fig27" ref-type="fig">27</xref></xref>) was
identified.</p><fig id="fig27" position="float"><label>Figure 27</label><caption><p>Primary SAR study at hit furyl amide <bold>145</bold> and
schematic
representation of enzyme pockets occupied by <bold>146</bold> and <bold>11</bold>.</p></caption><graphic xlink:href="jm5b01461_0028" id="gr27" position="float"></graphic></fig><p>Optimization study based
on derivatives (Ugi library) structurally
related to hit compound <bold>145</bold> resulted in a series of 3-pyridyl-based
inhibitors among which the two compounds, <bold>146</bold> and <bold>147</bold> (<xref rid="fig27" ref-type="fig">Figure <xref rid="fig27" ref-type="fig">27</xref></xref>), were shown to be active against SARS-CoV 3CL<sup>pro</sup>.</p><p>The X-ray crystal structure of <bold>146</bold> bound to SARS-CoV
3CL<sup>pro</sup> (<xref rid="fig28" ref-type="fig">Figure <xref rid="fig28" ref-type="fig">28</xref></xref>) demonstrated that the binding orientation of <bold>146</bold> was similar to that of known covalent peptidomimetic inhibitors
(for example compound <bold>11</bold>) and preferentially occupies
the S3–S1′ subpockets of SARS-CoV 3CL<sup>pro</sup> enzyme
as <italic>R</italic>-enantiomer. The <italic>tert</italic>-butyl
amide occupies the S3-pocket, the <italic>tert</italic>-butylanilido
group occupies the deep S2-pocket, and the 3-pyridyl moiety occupies
the S1; the furyl amide acts as a P1′ group. Inhibitor <bold>146</bold> lacks a reactive warhead.</p><fig id="fig28" position="float"><label>Figure 28</label><caption><p>X-ray crystal structure
of <bold>146</bold> bound to the binding
pocket SARS-CoV 3CL<sup>pro</sup> (PDB ID 3V3M). The pockets S1′–S3 are
highlighted, and the compound <bold>146</bold> is represented in stick
model and colored in cyan.</p></caption><graphic xlink:href="jm5b01461_0029" id="gr28" position="float"></graphic></fig><p>On the basis of the SAR for <bold>146</bold> and related
analogues,
first a chemical library focusing exclusively on the P1′ group
was synthesized while holding the P1–P3 groups constant. This
resulted in a series of inhibitors.<sup><xref ref-type="bibr" rid="ref110">110</xref></sup> The
SAR study around P1′ of <bold>146</bold> showed that the five-membered
π-excessive heterocycles proved the most successful <bold>148</bold>–<bold>153</bold> (<xref rid="fig29" ref-type="fig">Figure <xref rid="fig29" ref-type="fig">29</xref></xref>A). Especially, compound bearing imidazole (<bold>150</bold>) and 5-chlorofuran (<bold>152</bold>) analogue exhibited equipotent
to <bold>146</bold> with IC<sub>50</sub> values of 6.0 and 5.2 μM,
respectively. Next, the P1 3-pyridyl unit in <bold>146</bold> was
replaced with its isosteres in order to identify alternate hydrogen
bond acceptor groups. This effort led to identify another set of compounds
(<bold>154</bold>–<bold>156</bold>, <xref rid="fig29" ref-type="fig">Figure <xref rid="fig29" ref-type="fig">29</xref></xref>B). Among them, only pyridazine (<bold>154</bold>) and pyrazine (<bold>155</bold>) were tolerated, although no improvement
was found around the pyridyl ring over <bold>146</bold>. Both 2-and
4-pyridyl (<bold>156</bold>) analogues were not tolerable and reduced
the potency.<sup><xref ref-type="bibr" rid="ref110">110</xref></sup></p><fig id="fig29" position="float"><label>Figure 29</label><caption><p>SAR studies at the P1′
(A) and P1 sites (B) of <bold>146</bold> and chiral separation of <bold>146</bold>-(<italic>R</italic>,<italic>S</italic>) (C) to <bold>146</bold>-(<italic>R</italic>) and <bold>146</bold>-(<italic>S</italic>) enantiomers.</p></caption><graphic xlink:href="jm5b01461_0030" id="gr29" position="float"></graphic></fig><p>In a continuing study, the racemic
compound <bold>146</bold> was
purified by chiral supercritical fluid chromatography to separate <bold>146</bold>-(<italic>R</italic>) (ML188)<sup><xref ref-type="bibr" rid="ref110">110</xref></sup> and <bold>146</bold>-(<italic>S</italic>) enantiomers (<xref rid="fig29" ref-type="fig">Figure <xref rid="fig29" ref-type="fig">29</xref></xref>C). The evaluation
of a compound <bold>146</bold>-(<italic>R</italic>) exhibited inhibitory
activity with an IC<sub>50</sub> of 1.5 ± 0.3 μM against
SARS-CoV 3CL<sup>pro</sup>, while the other enantiomer <bold>146</bold>-(<italic>S</italic>) was inactive. The mechanism of inhibition of
SARS-CoV 3CL<sup>pro</sup> by <bold>146</bold>-(<italic>R</italic>) was determined to be competitive (<italic>K</italic><sub>i</sub>, 1.6 ± 0.26 μM) with noncovalent inhibition. Owing to
the excellent 3CL<sup>pro</sup> inhibition and antiviral activity
(12.9 ± 0.7 μM) against mock-infected and SARS-CoV infected
Vero E6 Cells, <bold>146</bold>-(<italic>R</italic>) was elected as
a first in class probe candidate from the furyl amide.</p><p>Following
the identification of probe compound <bold>146</bold>-(<italic>R</italic>), the same research group continued their further
efforts to develop potent, noncovalent SARS-CoV 3CL<sup>pro</sup> inhibitors
based upon a chemical class of benzotriazoles from MLPCN screening.<sup><xref ref-type="bibr" rid="ref112">112</xref></sup> This resulted in a hit compound <bold>157</bold> (<xref rid="fig30" ref-type="fig">Figure <xref rid="fig30" ref-type="fig">30</xref></xref>A) demonstrating
a SARS-CoV 3CL<sup>pro</sup> IC<sub>50</sub> of 6.2 μM and good
selectivity versus PL<sup>pro</sup> (IC<sub>50</sub> > 60 μM).</p><fig id="fig30" position="float"><label>Figure 30</label><caption><p>(A)
SAR studies at the P1, (B) P2–P1′, and (C) P3-truncation
of hit <bold>157</bold> to inhibitors (<bold>158</bold>–<bold>167</bold>).</p></caption><graphic xlink:href="jm5b01461_0031" id="gr30" position="float"></graphic></fig><p>The X-ray crystal structure
of <bold>157</bold> bound to SARS-CoV
3CL<sup>pro</sup> shows the diamide <bold>157</bold> binds into an
induced-fit binding site that is formed by a rearrangement of the
Gln189 and Met49 residue side chains (PDB ID 4MDS, <xref rid="fig31" ref-type="fig">Figure <xref rid="fig31" ref-type="fig">31</xref></xref>). This induced fit site accommodates
the <italic>syn</italic>-<italic>N</italic>-methyl pyrrole and anilido
acetamide moieties of the inhibitors within subpockets that can be
characterized as S2–S4 and S2–S1′ subpockets,
respectively. <xref rid="fig30" ref-type="fig">Figure <xref rid="fig30" ref-type="fig">30</xref></xref>A schematically illustrates the inhibitor-active site interactions
oriented in a similar manner as depicted in <xref rid="fig31" ref-type="fig">Figure <xref rid="fig31" ref-type="fig">31</xref></xref>.</p><fig id="fig31" position="float"><label>Figure 31</label><caption><p>X-ray crystal structure of <bold>157</bold> bound to SARS-CoV 3CL<sup>pro</sup> (PDB ID: 4MDS) is represented
in surface model. The compound <bold>157</bold> (green)
is shown in stick model, and the interacting residues (magenta) and
the binding pocket residues (gray) are shown in line model.</p></caption><graphic xlink:href="jm5b01461_0032" id="gr31" position="float"></graphic></fig><p>To improve the activity, first,
the SAR study focusing on benzotriazole
replacements in <bold>157</bold> for alternate hydrogen bond acceptor
functionality was demonstrated. This resulted the replacement of benzotriazole
with 4-phenyl 1,2,3-trizole <bold>158</bold> (IC<sub>50</sub> of 11
μM, <xref rid="fig30" ref-type="fig">Figure <xref rid="fig30" ref-type="fig">30</xref></xref>A) was tolerable.</p><p>Second, the acetamide modification (P2–P1′
region)
with a series of cyclic and acyclic congeners yielded many inhibitors
which show activities below 10 μM (<bold>159</bold>–<bold>162</bold>, <xref rid="fig30" ref-type="fig">Figure <xref rid="fig30" ref-type="fig">30</xref></xref>B), specifically, the branched <italic>i</italic>-propyl derivative
(<bold>159</bold>) and cyclobutylamide (<bold>160</bold>) having the
greatest activity below 5 μM.</p><p>Third, the researchers turned
to P3-truncation for minimum pharmacophore
to reduce overall molecular weight. This effort led to a series of
analogues and SAR proved that truncated amides (<bold>163</bold>–<bold>167</bold>, <xref rid="fig30" ref-type="fig">Figure <xref rid="fig30" ref-type="fig">30</xref></xref>C) have comparable activity versus the elaborated amides; for example,
compare <bold>163</bold>–<bold>167</bold> Vs <bold>159</bold>–<bold>162</bold>. The compound <bold>167</bold> represented
the first sub-100 nM inhibitor for the series and one of the most
potent nonwarhead based SARS-CoV 3CL<sup>pro</sup> inhibitors to date.</p><p>From the above compounds, one of the potent inhibitors, <bold>165</bold> (ML300)<sup><xref ref-type="bibr" rid="ref112">112</xref></sup> was selected for probe declaration.<sup><xref ref-type="bibr" rid="ref113">113</xref></sup> The biological profiles of inhibitors <bold>146</bold>-(<italic>R</italic>), <bold>160</bold>, and <bold>165</bold> are indicated in <xref rid="fig32" ref-type="fig">Figure <xref rid="fig32" ref-type="fig">32</xref></xref>. Relative to probe <bold>146</bold>-(<italic>R</italic>)
and the equipotent diamide <bold>160</bold>, the compound <bold>165</bold> proved to offer progresses in several areas. Inhibitor <bold>165</bold> is ∼100 amu lower MW (MW = 431) relative to <bold>160</bold> with moderate ligand efficiency (LE).<sup><xref ref-type="bibr" rid="ref114">114</xref></sup> Moderate cLogP value of <bold>165</bold> (cLogP = 3.2) greatly improves
ligand efficiency-dependent lipophilicity (LELP)<sup><xref ref-type="bibr" rid="ref114">114</xref></sup> versus <bold>146</bold>-(<italic>R</italic>) and <bold>160</bold>. When both probe <bold>146</bold>-(<italic>R</italic>)
and <bold>165</bold> tested in an in-house in vitro DMPK panel including
plasma protein binding, P450 enzyme inhibition, and intrinsic clearance
using liver microsomes, both <bold>146</bold>-(<italic>R</italic>)
and <bold>165</bold> possess good free fraction. However, intrinsic
clearance indicates both <bold>146</bold>-(<italic>R</italic>) and <bold>165</bold> are predicted to be highly cleared. <bold>146</bold>-(<italic>R</italic>) and <bold>165</bold> possess modest P450 enzyme inhibition,
with <bold>165</bold> maintaining 5–10 μM activity across
four major CYP enzymes (see <xref rid="fig32" ref-type="fig">Figure <xref rid="fig32" ref-type="fig">32</xref></xref>). Probe <bold>165</bold> was found to be highly selective
in a Eurofins lead-profiling screen,<sup><xref ref-type="bibr" rid="ref115">115</xref></sup> with only modest activity (10 μM) for melatonin MT1 receptor
in a radioligand binding assay.</p><fig id="fig32" position="float"><label>Figure 32</label><caption><p>Profiles of SARS-CoV 3CL<sup>pro</sup> inhibitors <bold>146</bold>-(<italic>R</italic>), <bold>160</bold>, and <bold>165</bold>.</p></caption><graphic xlink:href="jm5b01461_0033" id="gr32" position="float"></graphic></fig></sec></sec><sec id="sec6"><label>6</label><title>Metal Conjugated SARS-CoV 3CL<sup>pro</sup> Inhibitors</title><p>Metal ions have been shown to inhibit
many viral proteases such
as 3CL<sup>pro</sup> of noroviruses, papain-like protease (PLP2) of
SARS-CoV, human cytomegalovirus (hCMV) protease, and hepatitis C virus
(HCV) NS3 protease.<sup><xref ref-type="bibr" rid="ref116">116</xref>−<xref ref-type="bibr" rid="ref120">120</xref></sup> The screening of 960 metal conjugated compounds allowed inhibitors
with potent inhibitory activity against SARS-CoV 3CL<sup>pro</sup> to be identified. These include competitive inhibitors phenyl mercuric
acetate (<bold>168</bold>, <italic>K</italic><sub>i</sub> = 0.7 μM),
thimerosal (<bold>169</bold>, <italic>K</italic><sub>i</sub> = 2.4
μM), and phenyl mercuric nitrate (<bold>170</bold>, <italic>K</italic><sub>i</sub> = 0.3 μM) (<xref rid="fig33" ref-type="fig">Figure <xref rid="fig33" ref-type="fig">33</xref></xref>).<sup><xref ref-type="bibr" rid="ref121">121</xref>,<xref ref-type="bibr" rid="ref122">122</xref></sup> However, inhibition
was more pronounced using zinc-conjugated compounds (<bold>171</bold>–<bold>174</bold>), i.e., 1-hydroxypyridine-2-thione zinc
(<bold>171</bold>, <italic>K</italic><sub>i</sub> = 0.17 μM)
compared to Zn<sup>2+</sup> ions alone (<italic>K</italic><sub>i</sub> = 1.1 μM).</p><fig id="fig33" position="float"><label>Figure 33</label><caption><p>Metal-conjugated inhibitors and their inhibition potential
against
SARS-CoV 3CL<sup>pro</sup>.</p></caption><graphic xlink:href="jm5b01461_0034" id="gr33" position="float"></graphic></fig><p>The X-ray crystal structure of SARS-CoV 3CL<sup>pro</sup>–<bold>168</bold> (PDB ID 1Z1I) revealed that phenyl-bound mercury occupied
the S3 pocket, which
is responsible for its enzymatic activity. Hg(II) ions are known to
cause toxic effects because the affinity of Hg<sup>2+</sup> ions to
thiol groups in proteins leads to nonspecific inhibition of cellular
enzymes.<sup><xref ref-type="bibr" rid="ref123">123</xref></sup> However, regarding the structures
of zinc-centered complexes, the zinc ion plays a key role in targeting
the catalytic residues via binding to the His41–Cys145 catalytic
dyad to yield a zinc central tetrahedral geometry. This type of inhibition
was similar to the zinc-mediated serine protease inhibitor keto-BABIM-Zn<sup>2+</sup> for trypsin in that a zinc ion was coordinated to the two
chelating nitrogen atoms of bis(5-amidino-2-benimidazilyl)methane
(BABIM) and the two catalytic residues (His-Ser) of trypsin in the
tetrahedral geometry.<sup><xref ref-type="bibr" rid="ref124">124</xref></sup> The safety of
zinc-containing compounds for human use has been indicated by the
fact that zinc acetate and zinc sulfate are added as supplements to
drugs for the treatment of Wilson’s disease and Behcet’s
disease, respectively.<sup><xref ref-type="bibr" rid="ref125">125</xref>,<xref ref-type="bibr" rid="ref126">126</xref></sup> Moreover, the possibility
of zinc complexes incorporated into cells through the cell membrane
was also demonstrated by studies on type-2 diabetic treatment.<sup><xref ref-type="bibr" rid="ref127">127</xref></sup></p><p>Analysis of the active site cavity of
this SARS–cysteine
protease reveals the presence of a subsite contains a cluster of serine
residues (Ser139, Ser144, and Ser147) and is an attractive target
for the design of high affinity small molecule inhibitors. This cluster
is conserved in all known coronavirus proteases. In particular, Ser139
and Ser147 are conserved in all known coronavirus. Because of the
known potential reactivity of boronic acid compounds with the hydroxyl
group of the serine residue, a series of bifunctional boronic acid-conjugated
compounds (<bold>175</bold>–<bold>177</bold>) have been reported
against SARS-CoV 3CL<sup>pro</sup> enzyme (<xref rid="fig33" ref-type="fig">Figure <xref rid="fig33" ref-type="fig">33</xref></xref>).<sup><xref ref-type="bibr" rid="ref128">128</xref></sup> The greatest
improvement in affinity was achieved with an amide type compound (<bold>177</bold>) with a <italic>K</italic><sub>i</sub> of 40 nM. Isothermal
titration microcalorimetric experiments indicated that these inhibitors
bind reversibly to SARS-CoV 3CL<sup>pro</sup> in an enthalpically
favorable manner, implying that they establish strong interactions
with the protease molecule.</p></sec><sec id="sec7"><label>7</label><title>Miscellaneous SARS-CoV 3CL<sup>pro</sup> Inhibitors</title><p>Over the
past decade, in silico virtual screening (VS), in particular
structure-based virtual screening (SBVS), has emerged as a reliable,
cost-effective, and time-saving technique for the discovery of lead
compounds as an alternative to high throughput screening (HTPS).<sup><xref ref-type="bibr" rid="ref129">129</xref></sup> The application of VS to the discovery of new
enzyme inhibitors involves docking, computational fitting of the compound
structure to the active site of an enzyme, and scoring and ranking
of each compound.<sup><xref ref-type="bibr" rid="ref130">130</xref></sup> On the basis of the
structural information, 361413 structurally diverse small molecules
were screened by a “genome-to-drug-lead” approach. Compound <bold>178</bold> showed modest activity against targeted human SARS-CoV
3CL<sup>pro</sup> Toronto-2-strain with an EC<sub>50</sub> of 23 μM
(<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>). Virtual
screening of 50240 structurally diverse small molecules allowed 104
compounds with anti-SARS-CoV activities to be identified.<sup><xref ref-type="bibr" rid="ref131">131</xref></sup> Inhibitor <bold>179</bold> showed potent inhibitory
activity with an IC<sub>50</sub> value of 2.5 μM and an EC<sub>50</sub> of 7 μM in a Vero cell-based SARS-CoV plaque reduction
assay (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>).
Another group of researchers, using a quenched fluorescence resonance
energy transfer assay, screened 50000 drug-like molecules, resulting
in 572 hits.<sup><xref ref-type="bibr" rid="ref99">99</xref></sup> After applying a series
of virtual and experimental filters, five structurally novel molecules
were identified that showed potent inhibitory activity (IC<sub>50</sub> = 0.5–7 μM) against SARS-CoV 3CL<sup>pro</sup>.</p><fig id="fig34" position="float"><label>Figure 34</label><caption><p>Miscellaneous
SAR–CoV 3CL<sup>pro</sup> inhibitors.</p></caption><graphic xlink:href="jm5b01461_0035" id="gr34" position="float"></graphic></fig><p>Among them, compounds <bold>180</bold> (IC<sub>50</sub> =
4.3 μM)
and <bold>181</bold> (IC<sub>50</sub> = 4.3 μM) (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>) showed good inhibitory activity
of SARS-CoV 3CL<sup>pro</sup> and exhibited interesting selectivity
with no inhibition against other proteases tested (HAV 3C<sup>pro</sup>, NS3<sup>pro</sup>, chymotrypsin, and papain).<sup><xref ref-type="bibr" rid="ref99">99</xref></sup></p><p>The elucidation of the crystal structure of SARS-CoV
3CL<sup>pro</sup> provided enormous opportunities for the discovery
of inhibitors
through rational drug design. As part of an effort to discover small
molecule inhibitors of SARS-CoV 3CL<sup>pro</sup>, structure-based
virtual screening of 32000 small molecules was screened against the
SARS-CoV 3CL<sup>pro</sup> enzyme.<sup><xref ref-type="bibr" rid="ref47">47</xref></sup> Use
of knowledge-based filters yielded 27 molecules for follow-up. A biological
evaluation of the inhibitors in the low micromolar range found two
compounds, <bold>182</bold> and <bold>183</bold>, with IC<sub>50</sub> values of 18.2 and 17.2, respectively (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>). It has been reported that several nucleoside
derivatives have 6-chloropurine as a nucleobase showed potent antiviral
activity against some types of viruses.<sup><xref ref-type="bibr" rid="ref132">132</xref>,<xref ref-type="bibr" rid="ref133">133</xref></sup> Because 6-chloropurine analogues are known to inhibit bacterial
RNA polymerases, a series of nucleoside analogues with 6-chloropurines
were evaluated for anti-SARS-CoV activity by a plaque reduction activity.<sup><xref ref-type="bibr" rid="ref134">134</xref></sup> Among them, two compounds, <bold>184</bold> and <bold>185</bold>, exhibited modest anti-SARS-CoV activity (IC<sub>50</sub> values of 48.7 and 14.5 μM, respectively) that was
comparable to those of mizoribine and ribavirin (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>). This study revealed several
SAR trends such as a 6-chloropurine moiety, 5′-hydroxy, and
protected (benzylated)-5′-hydroxy group are responsible for
the potent inhibitory activity.</p><p>Ribavirin, a broad-spectrum
of inhibitor of RNA and DNA viruses,
was used for the treatment of SARS affected patients<sup><xref ref-type="bibr" rid="ref135">135</xref></sup> but it does not inhibit viral growth at concentrations
attainable in human serum. In contrast, interferon (IFN)-α showed
an in vitro inhibitory effect at concentrations of 1000 IU/mL.<sup><xref ref-type="bibr" rid="ref136">136</xref></sup> Interestingly, the combination of ribavirin
and IFN-β synergistically inhibited SARS-CoV replication. The
HIV protease inhibitor nelfinavir<sup><xref ref-type="bibr" rid="ref137">137</xref></sup> and
the antimalarial agent chloroquine<sup><xref ref-type="bibr" rid="ref138">138</xref></sup> showed
strong inhibitory activity against SARS-CoV replication. However,
no cytoprotective effect was found for nelfinavir in an independent
study.<sup><xref ref-type="bibr" rid="ref139">139</xref>,<xref ref-type="bibr" rid="ref140">140</xref></sup> Structure-based virtual screening of compounds
was conducted to identify novel SARS-CoV 3CL<sup>pro</sup> inhibitors.<sup><xref ref-type="bibr" rid="ref141">141</xref></sup> The top-ranked 1468 compounds with free binding
energy ranging from −14.0 to −17.09 kcal mol<sup>–1</sup> were selected to evaluate the hydrogen bond interactions in the
active site of SARS-CoV 3CL<sup>pro</sup>. Among them, 53 compounds
were selected for their inhibitory activity toward SARS-CoV 3CL<sup>pro</sup> from <italic>Escherichia coli</italic>. Two
of the compounds (<bold>186</bold> and <bold>187</bold>) were demonstrated
to be competitive inhibitors of 3CL<sup>pro</sup> with <italic>K</italic><sub>i</sub> values of 9.11 and 9.93 μM, respectively (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>).<sup><xref ref-type="bibr" rid="ref141">141</xref></sup> A detailed docking simulation analyses suggested
that these inhibitors could be stabilized by the formation of hydrogen
bonds with catalytic residues and the establishment of hydrophobic
contacts at the opposite region of the active site. In particular,
for the potent compound <bold>187</bold>, the nitrophenyl group was
likely to be very crucial in the SARS-CoV 3CL<sup>pro</sup> inhibitory
activity through its formation of H-bonds with Cys145 and Gly143,
as well as its hydrophobic interactions with His41 and Cys145.</p><p>Recently, the combination of virtual screening (VS) and high-throughput
screening (HTS) techniques were applied to screen 41000 compounds
from structurally diverse libraries have allowed novel, nonpeptidic
small molecule inhibitors (<bold>188</bold>, IC<sub>50</sub> = 13.9
μM) and (<bold>189</bold>, IC<sub>50</sub> = 18.2 μM)
against human SARS-CoV 3CL<sup>pro</sup> to be identified (<xref rid="fig34" ref-type="fig">Figure <xref rid="fig34" ref-type="fig">34</xref></xref>).<sup><xref ref-type="bibr" rid="ref142">142</xref></sup> Because the newly identified compounds are
of low molecular weight, they were examined for selectivity against
three proteases, namely SARS-CoV PL<sup>pro</sup> (a cysteine protease),
human UCH-L1 (a cysteine protease), and hepatitis C virus NS3/4A (a
serine protease), and two nonproteolytic enzymes, <italic>Bacillus
anthracis</italic> dihydroorotase and <italic>Streptococcus
pneumoniae</italic> PurC. Compound <bold>189</bold> displayed
good selectivity for SARS-CoV 3CL<sup>pro</sup> and did not show inhibitory
activity (>200 μM) against other five enzymes, whereas compound <bold>188</bold> showed 20-fold selectivity against the two SARS cysteine
proteases, 3CL<sup>pro</sup> and PL<sup>pro</sup>, over other enzymes.
Because low molecular weight compounds typically lack high specificity,
lack of inhibition of compound <bold>188</bold> for other enzymes,
especially the UCH-L1 cysteine protease, is particularly noteworthy.</p></sec><sec id="sec8"><label>8</label><title>Conclusion and Perspectives</title><p>The emergence of SARS and
the identification of a coronavirus as
the causative agent of the disease astounded the coronavirus community,
as it was the first definitive association of a coronavirus with a
severe disease in humans. Because the first crystal structure of the
SARS-CoV 3CL<sup>pro</sup> dimer with a peptidic CMK inhibitor covalently
bound was elucidated in 2003, over 20 crystal structures of the enzyme
have been reported. Structure-based design and virtual screens have
provided both peptidomimetic and nonpeptidomimetic inhibitors with
potency in the micromolar to nanomolar range. Yet, to date, there
is no effective therapy for the treatment of SARS in humans, and to
our knowledge, no CoV 3CL<sup>pro</sup> inhibitor has been taken into
clinical development. In this perspective, we have described the SAR
for several classes of inhibitors, highlighting their structural features
and binding modes. Both peptidomimetic and small molecule SARS-CoV
3CL<sup>pro</sup> are largely based on a warhead-based design strategy.
So far, only a few inhibitors have been described that exhibit good
enzymatic and cellular potency, and the majority of these inhibitors
have not been followed up with additional studies (such as antiviral
activity or in vivo evaluation), likely due to their unattractive
structures and/or their nonideal physiochemical properties.</p><p>The reactive warhead groups used in peptidomimetic inhibitors for
SARS-CoV 3CL<sup>pro</sup> include Michael acceptors, aldehydes, epoxy
ketones, electrophilic ketones such as halomethyl ketones, and trifluoromethyl
ketones. Although these peptidomimetics are covalent inhibitors with
the potential for toxicity, significant improvements have been made
in enzymatic and cellular potency.</p><p>Of the many peptidomimetics
inhibitors described in the literature,
those highlighted in <xref rid="fig35" ref-type="fig">Figure <xref rid="fig35" ref-type="fig">35</xref></xref> appear to be the most promising for further optimization
efforts. Compound <bold>2</bold> (<xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref>) is an example of an inhibitor incorporating
a Michael acceptor. It was developed by Pfizer as an inhibitor of
human rhinovirus 3C protease for common cold (targeted rhinovirus
3C-protease). Although <bold>2</bold> was not active against SARS-CoV
in cell culture, it served as a good starting point for anti-SARS
drug design, leading to inhibitors <bold>8</bold> and <bold>18</bold> (see <xref rid="sec4.1" ref-type="other">section <xref rid="sec4.1" ref-type="other">4.1</xref></xref>), which are the two most potent inhibitors against SARS-CoV 3CL<sup>pro</sup> incorporating a Michael acceptor warhead. Specifically,
compound <bold>8</bold> exhibited excellent cellular potency with
an EC<sub>50</sub> value of 0.18 μM and it is a nontoxic anti-SARS
agent. However, further in vivo studies for compound <bold>8</bold> have not been reported in the literature.</p><fig id="fig35" position="float"><label>Figure 35</label><caption><p>Profile of representative
peptidic SARS-CoV 3CL<sup>pro</sup> inhibitors
highlighting reactive warhead groups (red).</p></caption><graphic xlink:href="jm5b01461_0036" id="gr35" position="float"></graphic></fig><p>Peptidic aldehydes are promising enzymatic inhibitors, but
they
are unlikely to be effective as therapeutic agents due to their rapid
in vivo metabolism and low oral bioavailability. In contrast, the
peptide aldehyde thrombin inhibitor efegatran was well tolerated in
a phase I clinical trial.<sup><xref ref-type="bibr" rid="ref143">143</xref>,<xref ref-type="bibr" rid="ref144">144</xref></sup> Inhibitor <bold>45</bold>, a potent peptide aldehyde, showed remarkable activity against SARS-CoV
and human coronavirus (HCoV) 229E replications, reducing the viral
titer by 4.7 log (at 5 μM) for SARS-CoV and 5.2 log (at 1.25
μM) for HCoV 229E. This inhibitor also displayed a stable profile
in mouse, rat, and human plasma (see <xref rid="sec4.5" ref-type="other">section <xref rid="sec4.5" ref-type="other">4.5</xref></xref>) and may represent a starting point for
the development of an anti-SARS agent.</p><p>Inhibitor <bold>51</bold> is one of the potent inhibitors in the
halomethyl series, exhibiting low toxicity in mice after a single
ip dose at 25, 50, and 100 mg/kg, no weight loss, behavioral changes,
or gross pathology of major organs was observed at the tested doses
(see <xref rid="sec4.6" ref-type="other">section <xref rid="sec4.6" ref-type="other">4.6</xref></xref>).
The low molecular weight of <bold>51</bold> is a potential advantage.
Because peptidyl monofluoromethyl ketones have been shown to be effective
in vivo,<sup><xref ref-type="bibr" rid="ref145">145</xref>−<xref ref-type="bibr" rid="ref147">147</xref></sup> the inhibitor <bold>51</bold> may be a suitable
candidate for further in vivo efficacy and toxicology studies.</p><p>Numerous small molecules were also discussed in this perspective.
The majority of efforts to develop nonpeptide SARS-CoV 3CL<sup>pro</sup> inhibitors have also relied on warhead-based design strategy, and
several of these nonpeptide inhibitors achieved nanomolar potency.
The most interesting inhibitors (<bold>78</bold>, <bold>116</bold>, <bold>119</bold>, <bold>124</bold>, <bold>129</bold>, <bold>146</bold>, <bold>160</bold>, <bold>165</bold>, and <bold>186</bold>) are illustrated
in <xref rid="fig36" ref-type="fig">Figure <xref rid="fig36" ref-type="fig">36</xref></xref>. In the
case of pyridyl esters, the potent mechanism-based enzyme inactivator <bold>124</bold> (see <xref rid="sec5.6" ref-type="other">section <xref rid="sec5.6" ref-type="other">5.6</xref></xref>) achieved cell-based inhibition below 10 μM in SARS-CoV
infected Vero E6 cells. Compounds <bold>146</bold>-(<italic>R</italic>), <bold>160</bold>, and <bold>165</bold> are promising examples
of noncovalent SARS-CoV 3CL<sup>pro</sup> inhibitors of moderate molecular
weights and good enzymatic and antiviral activity (see <xref rid="sec5.10" ref-type="other">section <xref rid="sec5.10" ref-type="other">5.10</xref></xref>). These inhibitors
are potential starting points for the design of more potent 3CL<sup>pro</sup> inhibitors with a noncovalent mechanism of action. However,
further in vivo studies for above-mentioned small molecules have not
reported so far.</p><fig id="fig36" position="float"><label>Figure 36</label><caption><p>Profile of representative nonpeptidic SARS-CoV 3CL<sup>pro</sup> inhibitors highlighting reactive warhead groups (red).</p></caption><graphic xlink:href="jm5b01461_0037" id="gr36" position="float"></graphic></fig><p>Although many structural and nonstructural
proteins are known to
be potential targets for anticoronavirus therapy, none of them are
well-conserved due to their possible role in the viral life cycle,
thus limiting the potential success of wide-spectrum inhibitors. In
contrast, the coronavirus 3CL<sup>pro</sup> is highly conserved among
coronaviruses, making it an attractive target for broad-spectrum inhibitors
(see SI, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">Table S1</ext-link>).<sup><xref ref-type="bibr" rid="ref148">148</xref></sup> The proteases share 40–60% sequence identity and
60–100% sequence similarity. Therefore, targeting SARS-CoV
3CL<sup>pro</sup> is an important approach for the development of
antiviral therapy that can be applied for broad viral infections.
Recent reports have revealed that many SARS-CoV 3CL<sup>pro</sup> inhibitors
showed potential activity against the recent outbreak of MERS-CoV.<sup><xref ref-type="bibr" rid="ref149">149</xref></sup></p><p>A feasible and rapid advancement in the
drug discovery for the
development of effective chemotherapeutics against SARS-CoV might
be achieved by repurposing existing and clinically approved drugs.
It was recently reported that screening a library of drugs either
clinically developed or with a well-defined cellular pathway from
different classes of therapeutics produced a series of compounds with
good activity against SARS-CoV.<sup><xref ref-type="bibr" rid="ref149">149</xref></sup> Drugs
that inhibit CoV included neurotransmitter inhibitors, estrogen receptor
antagonists, kinase signaling inhibitors, protein-processing inhibitors,
inhibitors of lipid or sterol metabolism, and inhibitors of DNA synthesis
or pair. However, the inhibitors (peptidomimetics or nonpeptidomimetics)
that target other serine proteases (e.g., HCV protease, thrombin)
and cysteine proteases (e.g., calpain, cathepsin K, caspases) have
not been tested against 3CL<sup>pro</sup>. For examples, ketoamides
(such as A-705253 for calpain),<sup><xref ref-type="bibr" rid="ref150">150</xref></sup> nitriles
(such as odanacatib/MK-0822 and vildagliptin/LAF237 for cathepsin
K and dipeptidyl peptidase-4 (DPP4)),<sup><xref ref-type="bibr" rid="ref151">151</xref>,<xref ref-type="bibr" rid="ref152">152</xref></sup> phenyloxymethyl
ketones (such as VX-166 for caspases),<sup><xref ref-type="bibr" rid="ref153">153</xref></sup> fused triazole derivatives (such as sitagliptin/MK-0431 for DPP4),<sup><xref ref-type="bibr" rid="ref154">154</xref></sup> nonpeptides (such as apixaban/BMS-562247-01
for factor Xa),<sup><xref ref-type="bibr" rid="ref155">155</xref></sup> and beta lactams for
penicillin binding proteins such as penicillin.<sup><xref ref-type="bibr" rid="ref156">156</xref></sup> Therefore, these structural types should be considered
in future for the development of anti-SARS therapy.</p><p><italic>N</italic>-Finger residues (<italic>N</italic>-finger)
of SARS 3CL<sup>pro</sup> play an important role in enzyme dimerization,
and therefore peptides with <italic>N</italic>-terminal amino acid
sequences may act as inhibitors of 3CL<sup>pro</sup> dimerization,
similar HIV protease, and other viral enzymes.<sup><xref ref-type="bibr" rid="ref157">157</xref>−<xref ref-type="bibr" rid="ref163">163</xref></sup> In 2006, Wei et al. reported that <italic>N</italic>-terminal octapeptide
N8 (<italic>K</italic><sub>i</sub> of 2.20 mM) was the first example
of inhibitor targeting the dimeric interface of SARS 3CL<sup>pro</sup>,<sup><xref ref-type="bibr" rid="ref164">164</xref></sup> providing a novel strategy for drug
design against SARS and other coronaviruses. However, no peptidomimetic
or small molecule inhibitor has yet been reported in the literature.
Although it would be a great challenge to explore new inhibitors of
dimerization, with the current development of computational approaches,
the structure-based design of novel inhibitors may be successful.</p><p>In conclusion, although huge efforts have been taken by both academia
and pharmaceutical industries, no coronavirus protease inhibitor has
yet successfully completed a preclinical development program. We hope
that this perspective will be useful to medicinal chemists targeting
3CL<sup>pro</sup> to identify novel anti-SARS CoV inhibitors with
drug-like properties and that effective therapy for coronaviruses
will be discovered.</p></sec></body><back><notes id="notes-2" notes-type="si"><title>Supporting Information Available</title><p>The Supporting Information
is available free of charge on the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org">ACS Publications website</ext-link> at DOI: <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01461">10.1021/acs.jmedchem.5b01461</ext-link>.</p><list id="silist" list-type="simple"><list-item><p>Docking figures
of compounds <bold>18</bold>, <bold>41</bold>–<bold>44</bold>, <bold>45</bold>, <bold>46</bold>, <bold>83</bold>, <bold>92</bold>, <bold>112</bold>, and <bold>155</bold>; sequence comparison analysis
of 3CL<sup>pro</sup> of coronaviruses
to the SARS-CoV 3CL<sup>pro</sup>; list of X-ray structures of ligands
with 3C<sup>pro</sup> and 3CL<sup>pro</sup> (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01461/suppl_file/jm5b01461_si_001.pdf">PDF</ext-link>)</p></list-item></list></notes><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="sifile1"><media xlink:href="jm5b01461_si_001.pdf"><caption><p>jm5b01461_si_001.pdf</p></caption></media></supplementary-material></sec><notes notes-type="COI-statement" id="notes-1"><p>The authors
declare no competing financial interest.</p></notes><bio id="BIO-d268e6000-autogenerated" rid="ath1"><p><bold>Thanigaimalai Pillaiyar</bold> received his Master’s
degree in Chemistry in 2006 from Bharathiar University, India. Prior
to his doctoral study, he worked as a Research Executive at Orchid
Chemicals and Pharmaceuticals Limited, India. He received his Doctoral
degree in Medicinal Chemistry in 2011 under the supervision of Prof.
Dr. Sang-Hun Jung at Chungnam National University, South Korea. In
2011, he won a “Japanese Society for the Promotion of Science
Postdoctoral fellowship” for two years with Prof. Dr. Yoshio
Hayashi at Tokyo University of Pharmacy and Life sciences, Japan.
He was awarded an Alexander von Humboldt Postdoctoral fellowship”
in 2013 for two years with Prof. Dr. Christa E. Müller at University
of Bonn, Germany. He has been working on various therapeutic targets,
focusing on infective and inflammatory diseases.</p></bio><bio id="BIO-d268e6005-autogenerated" rid="ath2"><p><bold>Manoj Manickam</bold> received his Ph.D. in 2010
from Bharathiar
University under the supervision of Prof. Dr. K. J. Rajendra Prasad,
Coimbatore, India. He continued to work as a Research Associate at
Orchid Chemicals and Pharmaceuticals Ltd. Then he moved to Chungam
National University, South Korea, for continuing his research. Currently,
he is a Senior Research Scientist at the Department of Pharmacy and
Institute of Drug Research and Development, Chungnam National University,
working with Professor Sang-Hun Jung.</p></bio><bio id="BIO-d268e6010-autogenerated" rid="ath3"><p><bold>Vigneshwaran Namasivayam</bold> is a Scientific Staff at
Pharmaceutical Institute, University of Bonn, Germany (since 2010),
and involved in the field of cheminformatics, computational chemistry,
and molecular modelling. He gained his Master of Technology in Bioinformatics
from SASTRA University, India (2004), and Doctoral degree under the
supervision of Prof. Dr. Hans-Jörg Hofmann from Leipzig University,
Germany (2009). He carried out his postdoctoral research at Technical
University of Munich, Germany (2010). Prior to his doctoral studies
in Germany, he worked as a Research Executive (2004–2006) at
Orchid Chemical and Pharmaceutical Limited, Chennai, India.</p></bio><bio id="BIO-d268e6015-autogenerated" rid="ath4"><p><bold>Yoshio Hayashi</bold> earned his Ph.D. in
1990 in the Faculty
of Pharmaceutical Science, Kyoto University, under the guidance of
Emeritus Prof. Haruaki Yajima and Prof. Nobutaka Fujii. After spending
two years at Calpis Food Industry Co., Ltd. and three years at Nippon
Steel Corporation (NSC) as a researcher, he was promoted to senior
researcher at the Life Science Research Center of the NSC, where he
stayed for another eight years. In 1999, he joined Prof. Yoshiaki
Kiso’s group in the Department of Medicinal Chemistry of Kyoto
Pharmaceutical University as a lecturer and, in 2001, was appointed
as an associate professor. In 2007, he moved to Tokyo University of
Pharmacy and Life Sciences as a full professor. His research interests
include peptide chemistry, peptidomimetics, and medicinal chemistry.</p></bio><bio id="BIO-d268e6020-autogenerated" rid="ath5"><p><bold>Sang-Hun Jung</bold> received his M.S.
degree from the College
of Pharmacy of the Seoul National University in 1976. He received
his Ph.D. from the Chemistry Department at the University of Houston,
USA, in 1984. He served as a postdoctoral fellow at the University
of Pittsburgh until 1985 and as a Principle investigator of LG life
Science from 1985 to 1989. He has been a professor at the College
of Pharmacy, Chungnam National University, South Korea, since 1989.
He has served as a Department Chairman (1993–2000), Dean of
the College of Pharmacy (2003–2004), and President of Institute
of Drug Research and Development of Chungnam National University (2007–2009).
His research interests include antimicrotubule-based anticancer agents,
novel inotropes with selective activation of cardiac myosin, and melanogenesis
inhibitors.</p></bio><ack><title>Acknowledgments</title><p>T.P. thanks the Japanese
Society for the Promotion of Science
(JSPS) foundation for a support for postdoctoral study in Japan. We
thank Proceedings of the National Academy of Sciences (PNAS) for the
permission to use <xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref></xref>.</p></ack><glossary id="dl1"><def-list><title>Abbreviations Used</title><def-item><term>hCoV</term><def><p>human coronavirus</p></def></def-item><def-item><term>SARS</term><def><p>severe acute respiratory
syndrome</p></def></def-item><def-item><term>Pros</term><def><p>proteases</p></def></def-item><def-item><term>TGEV</term><def><p>transmissible
gastroenteritis virus</p></def></def-item><def-item><term>IBV</term><def><p>infectious bronchitis virus</p></def></def-item><def-item><term>BCoV</term><def><p>bovine coronavirus</p></def></def-item><def-item><term>hCMV</term><def><p>human cytomegalovirus</p></def></def-item><def-item><term>HCV</term><def><p>hepatitis C virus</p></def></def-item><def-item><term>MHV</term><def><p>murine coronavirus mouse hepatitis
virus</p></def></def-item><def-item><term>WHO</term><def><p>World
Health Organization</p></def></def-item><def-item><term>MERS</term><def><p>Middle East respiratory syndrome</p></def></def-item><def-item><term>FDA</term><def><p>Food and Drug Administration</p></def></def-item><def-item><term>RNA</term><def><p>ribonucleic acid</p></def></def-item><def-item><term>DNA</term><def><p>DNA</p></def></def-item><def-item><term>PLP</term><def><p>papain-like cysteine protease</p></def></def-item><def-item><term>3CL<sup>pro</sup></term><def><p>chymotrypsin-like
cysteine protease</p></def></def-item><def-item><term>M<sup>pro</sup></term><def><p>main protease</p></def></def-item><def-item><term>APEs</term><def><p>aza-peptide epoxides</p></def></def-item><def-item><term>HPLC</term><def><p>high performance liquid chromatography</p></def></def-item><def-item><term>HIV</term><def><p>human immunodeficiency
virus</p></def></def-item><def-item><term>HCoV-229E</term><def><p>human coronavirus 229E</p></def></def-item><def-item><term>SAR</term><def><p>structure–activity relationship</p></def></def-item><def-item><term>QSAR</term><def><p>quantitative structure–activity
relationship</p></def></def-item><def-item><term>Cys</term><def><p>cysteine</p></def></def-item><def-item><term>His</term><def><p>histidine</p></def></def-item><def-item><term>Ser</term><def><p>serine</p></def></def-item><def-item><term>S</term><def><p>spike protein</p></def></def-item><def-item><term>M</term><def><p>membrane protein</p></def></def-item><def-item><term>N</term><def><p>nuleocapsid</p></def></def-item><def-item><term>E</term><def><p>envelope</p></def></def-item><def-item><term>BABIM</term><def><p>bis(5-amidino-2-benimidazilyl)methane</p></def></def-item><def-item><term>SBVS</term><def><p>structure-based
virtual screening</p></def></def-item><def-item><term>HTPS</term><def><p>high throughput screening</p></def></def-item><def-item><term>IFN</term><def><p>interferon</p></def></def-item><def-item><term>ORF</term><def><p>open reading frame</p></def></def-item><def-item><term>MW</term><def><p>molecular weight</p></def></def-item><def-item><term>LELP</term><def><p>ligand efficiency-dependent lipophilicity</p></def></def-item><def-item><term>LE</term><def><p>ligand efficiency</p></def></def-item><def-item><term>DPP4</term><def><p>dipeptidyl peptidase-4</p></def></def-item></def-list></glossary><ref-list><title>References</title><ref id="ref1"><mixed-citation publication-type="journal" id="cit1"><name><surname>Cheever</surname><given-names>F. S.</given-names></name>; <name><surname>Daniels</surname><given-names>J. B.</given-names></name>; <name><surname>Pappenheimer</surname><given-names>A. M.</given-names></name>; <name><surname>Baily</surname><given-names>O. T.</given-names></name><article-title>A murine virus (JHM)
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