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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Drug targets for corona virus: A systematic review</title>
<author><name sortKey="Prajapat, Manisha" sort="Prajapat, Manisha" uniqKey="Prajapat M" first="Manisha" last="Prajapat">Manisha Prajapat</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sarma, Phulen" sort="Sarma, Phulen" uniqKey="Sarma P" first="Phulen" last="Sarma">Phulen Sarma</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shekhar, Nishant" sort="Shekhar, Nishant" uniqKey="Shekhar N" first="Nishant" last="Shekhar">Nishant Shekhar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name>
<affiliation><nlm:aff id="aff2"><italic>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinha, Shweta" sort="Sinha, Shweta" uniqKey="Sinha S" first="Shweta" last="Sinha">Shweta Sinha</name>
<affiliation><nlm:aff id="aff3"><italic>Department of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhattacharyya, Anusuya" sort="Bhattacharyya, Anusuya" uniqKey="Bhattacharyya A" first="Anusuya" last="Bhattacharyya">Anusuya Bhattacharyya</name>
<affiliation><nlm:aff id="aff4"><italic>Departments of Ophthalmology, Government Medical College and Hospital, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bansal, Seema" sort="Bansal, Seema" uniqKey="Bansal S" first="Seema" last="Bansal">Seema Bansal</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">32201449</idno>
<idno type="pmc">7074424</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074424</idno>
<idno type="RBID">PMC:7074424</idno>
<idno type="doi">10.4103/ijp.IJP_115_20</idno>
<date when="2020">2020</date>
<idno type="wicri:Area/Pmc/Corpus">000B00</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B00</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Drug targets for corona virus: A systematic review</title>
<author><name sortKey="Prajapat, Manisha" sort="Prajapat, Manisha" uniqKey="Prajapat M" first="Manisha" last="Prajapat">Manisha Prajapat</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sarma, Phulen" sort="Sarma, Phulen" uniqKey="Sarma P" first="Phulen" last="Sarma">Phulen Sarma</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shekhar, Nishant" sort="Shekhar, Nishant" uniqKey="Shekhar N" first="Nishant" last="Shekhar">Nishant Shekhar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Avti, Pramod" sort="Avti, Pramod" uniqKey="Avti P" first="Pramod" last="Avti">Pramod Avti</name>
<affiliation><nlm:aff id="aff2"><italic>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sinha, Shweta" sort="Sinha, Shweta" uniqKey="Sinha S" first="Shweta" last="Sinha">Shweta Sinha</name>
<affiliation><nlm:aff id="aff3"><italic>Department of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kaur, Hardeep" sort="Kaur, Hardeep" uniqKey="Kaur H" first="Hardeep" last="Kaur">Hardeep Kaur</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Subodh" sort="Kumar, Subodh" uniqKey="Kumar S" first="Subodh" last="Kumar">Subodh Kumar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bhattacharyya, Anusuya" sort="Bhattacharyya, Anusuya" uniqKey="Bhattacharyya A" first="Anusuya" last="Bhattacharyya">Anusuya Bhattacharyya</name>
<affiliation><nlm:aff id="aff4"><italic>Departments of Ophthalmology, Government Medical College and Hospital, Chandigarh, India</italic>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kumar, Harish" sort="Kumar, Harish" uniqKey="Kumar H" first="Harish" last="Kumar">Harish Kumar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bansal, Seema" sort="Bansal, Seema" uniqKey="Bansal S" first="Seema" last="Bansal">Seema Bansal</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Medhi, Bikash" sort="Medhi, Bikash" uniqKey="Medhi B" first="Bikash" last="Medhi">Bikash Medhi</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Indian Journal of Pharmacology</title>
<idno type="ISSN">0253-7613</idno>
<idno type="eISSN">1998-3751</idno>
<imprint><date when="2020">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><p>The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21<sup>th</sup>
century. However, the lack of specific drugs to prevent/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines/drugs.</p>
</div>
</front>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Indian J Pharmacol</journal-id>
<journal-id journal-id-type="iso-abbrev">Indian J Pharmacol</journal-id>
<journal-id journal-id-type="publisher-id">IJPharm</journal-id>
<journal-title-group><journal-title>Indian Journal of Pharmacology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0253-7613</issn>
<issn pub-type="epub">1998-3751</issn>
<publisher><publisher-name>Wolters Kluwer - Medknow</publisher-name>
<publisher-loc>India</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32201449</article-id>
<article-id pub-id-type="pmc">7074424</article-id>
<article-id pub-id-type="publisher-id">IJPharm-52-56</article-id>
<article-id pub-id-type="doi">10.4103/ijp.IJP_115_20</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Systematic Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Drug targets for corona virus: A systematic review</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Prajapat</surname>
<given-names>Manisha</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="author-notes" rid="fn1">#</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sarma</surname>
<given-names>Phulen</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="author-notes" rid="fn1">#</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shekhar</surname>
<given-names>Nishant</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="author-notes" rid="fn1">#</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Avti</surname>
<given-names>Pramod</given-names>
</name>
<xref ref-type="aff" rid="aff2">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sinha</surname>
<given-names>Shweta</given-names>
</name>
<xref ref-type="aff" rid="aff3">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaur</surname>
<given-names>Hardeep</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Subodh</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bhattacharyya</surname>
<given-names>Anusuya</given-names>
</name>
<xref ref-type="aff" rid="aff4">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Harish</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bansal</surname>
<given-names>Seema</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Medhi</surname>
<given-names>Bikash</given-names>
</name>
<xref ref-type="aff" rid="aff1"></xref>
<xref ref-type="corresp" rid="cor1"></xref>
</contrib>
</contrib-group>
<aff id="aff1"><italic>Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</aff>
<aff id="aff2"><label>1</label>
<italic>Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</aff>
<aff id="aff3"><label>2</label>
<italic>Department of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India</italic>
</aff>
<aff id="aff4"><label>3</label>
<italic>Departments of Ophthalmology, Government Medical College and Hospital, Chandigarh, India</italic>
</aff>
<author-notes><corresp id="cor1"><bold>Address for correspondence:</bold>
Dr. Bikash Medhi, Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. E-mail: <email xlink:href="drbikashus@yahoo.com">drbikashus@yahoo.com</email>
</corresp>
<fn id="fn1"><label>#</label>
<p><italic>Equal contribution</italic>
.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><season>Jan-Feb</season>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>11</day>
<month>3</month>
<year>2020</year>
</pub-date>
<volume>52</volume>
<issue>1</issue>
<fpage>56</fpage>
<lpage>65</lpage>
<history><date date-type="received"><day>13</day>
<month>2</month>
<year>2020</year>
</date>
<date date-type="rev-recd"><day>23</day>
<month>2</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>25</day>
<month>2</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>Copyright: © 2020 Indian Journal of Pharmacology</copyright-statement>
<copyright-year>2020</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0"><license-p>This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.</license-p>
</license>
</permissions>
<abstract><p>The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21<sup>th</sup>
century. However, the lack of specific drugs to prevent/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines/drugs.</p>
</abstract>
<kwd-group><kwd>Coronavirus</kwd>
<kwd>drug targets</kwd>
<kwd>Middle East respiratory syndrome</kwd>
<kwd>severe acute respiratory syndrome</kwd>
</kwd-group>
</article-meta>
</front>
<body><sec sec-type="intro" id="sec1-1"><title>Introduction</title>
<p>Coronaviruses (CoVs) have a single-stranded RNA genome (size range between 26.2 and 31.7 kb, positive sense), covered by an enveloped structure.[<xref rid="ref1" ref-type="bibr">1</xref>
] The shape is either pleomorphic or spherical, and it is characterized by bears club-shaped projections of glycoproteins on its surface (diameter 80–120 nm).[<xref rid="ref1" ref-type="bibr">1</xref>
] Among all the RNA viruses, the RNA genome of CoV is one among the largest.[<xref rid="ref2" ref-type="bibr">2</xref>
] The number of open reading frames (ORFs) in the CoV genome ranges from six to ten.[<xref rid="ref2" ref-type="bibr">2</xref>
] CoV genetic material is susceptible for frequent recombination process, which can give rise to new strains with alteration in virulence.[<xref rid="ref3" ref-type="bibr">3</xref>
] There are seven strains of human CoVs, which include 229E, NL63, OC43, HKU1, Middle East respiratory syndrome (MERS)-CoV, severe acute respiratory syndrome (SARS)-CoV, and 2019-novel coronavirus (nCoV), responsible for the infection with special reference to the involvement of the respiratory tract (both lower and upper respiratory tract), e.g., common cold, pneumonia, bronchiolitis, rhinitis, pharyngitis, sinusitis, and other system symptoms such as occasional watery and diarrhea.[<xref rid="ref4" ref-type="bibr">4</xref>
<xref rid="ref5" ref-type="bibr">5</xref>
] Among these seven strains, three strains proved to be highly pathogenic (SARS-CoV, MERS-CoV, and 2019-nCoV), which caused endemic of severe CoV disease.[<xref rid="ref5" ref-type="bibr">5</xref>
] The reservoir of SARS-CoV is unknown, but bats and subsequent spread to Himalayan palm civets are hypothesized.[<xref rid="ref6" ref-type="bibr">6</xref>
] MERS-CoV also has a zoonotic origin in the Middle East, and the transmission is through camels.[<xref rid="ref7" ref-type="bibr">7</xref>
] Among these, the SARS-CoV outbreak started in 2003 in Guangdong province of China and the second outbreak of the MERS-CoV outbreak in 2012 in Saudi Arabia.[<xref rid="ref1" ref-type="bibr">1</xref>
<xref rid="ref4" ref-type="bibr">4</xref>
<xref rid="ref6" ref-type="bibr">6</xref>
] Previous to these two attacks, CoV was known to cause milder disease, and these two outbreaks highlighted their adaptive potential to the changing environmental conditions and they are classified under “emerging viruses.” Knowledge about the structure, metabolic pathways of CoV, and pathophysiology of CoV-associated diseases is important to identify possible drug targets.[<xref rid="ref8" ref-type="bibr">8</xref>
]</p>
<p>The most important structural proteins of CoV are spike (S) protein (trimeric), membrane (M) protein, envelop (E) protein, and the nucleocapsid (N) protein. Some of the viruses such as beta-CoVs also have hemagglutinin esterase (HE) glycoprotein.[<xref rid="ref3" ref-type="bibr">3</xref>
] The RNA genome of CoV has seven genes that are conserved in the order: ORF1a, ORF1b, S, OEF3, E, M, N in 5' to 3' direction. The two-third part of the RNA genome is covered by the ORF1a/b, which produces the two viral replicase proteins that are polyproteins (PP1a and PP1ab).[<xref rid="ref9" ref-type="bibr">9</xref>
] Sixteen mature nonstructural proteins (NSPs) arise from further processing of these two PPs. These NSPs take part in different viral functions including the formation of the replicase transcriptase complex. The remaining genome part of the virus encodes the mRNA which produces the structural proteins, i.e., spike, envelope, membrane, and nucleocapsid, and other accessory proteins.[<xref rid="ref9" ref-type="bibr">9</xref>
] Another important envelop-associated protein which is expressed by only some strains of CoV is the HE protein.[<xref rid="ref10" ref-type="bibr">10</xref>
] The RNA genome of CoV is packed in the nucleocapsid protein and further covered with envelope.[<xref rid="ref11" ref-type="bibr">11</xref>
]</p>
</sec>
<sec id="sec1-2"><title>Molecular Basics of Transmission of Coronavirus</title>
<p>In case of SARS-CoV, transmission is through droplet infection (respiratory secretions) and close person-to-person contact.[<xref rid="ref11" ref-type="bibr">11</xref>
<xref rid="ref12" ref-type="bibr">12</xref>
] It can also spread through sweat, stool, urine, and respiratory secretions.[<xref rid="ref13" ref-type="bibr">13</xref>
] When virus enters into the body, it binds to the primary target cells such as enterocytes and pneumocytes,[<xref rid="ref11" ref-type="bibr">11</xref>
<xref rid="ref12" ref-type="bibr">12</xref>
] thereby establishing a cycle of infection and replication. Other target cells of CoV are epithelial renal tubules, tubular epithelial cells of kidney, immune cells, and cerebral neuronal cells.[<xref rid="ref11" ref-type="bibr">11</xref>
<xref rid="ref12" ref-type="bibr">12</xref>
]</p>
<p>CoV attaches to the target cells with the help of spike protein–host cell protein interaction (angiotensin converting enzyme-2 [ACE-2] interaction in SARS-CoV[<xref rid="ref14" ref-type="bibr">14</xref>
] and dipeptidyl peptidase-4 [DPP-4] in MERS-CoV[<xref rid="ref15" ref-type="bibr">15</xref>
]). After the receptor recognition, the virus genome with its nucleocapsid is released into the cytoplasm of the host cells. The viral genome contains ORF1a and ORF1b genes, which produce two PPs that are pp1a and pp1b,[<xref rid="ref16" ref-type="bibr">16</xref>
] which help to take command over host ribosomes for their own translation process.[<xref rid="ref17" ref-type="bibr">17</xref>
] Both pp1a and pp1b take part in the formation of the replication transcription complex.[<xref rid="ref16" ref-type="bibr">16</xref>
] After processing of PP by protease, it produces 16 NSPs. All NSPs have their own specific functions such as suppression of host gene expression by NSP1 and NSP2, formation of a multidomain complex by NSP3, NSP5 which is a M protease which has role in replication,[<xref rid="ref17" ref-type="bibr">17</xref>
] NSP4 and NSP6 which are transmembrane (TM) proteins,[<xref rid="ref18" ref-type="bibr">18</xref>
] NSP7 and NSP8 which act as a primase,[<xref rid="ref16" ref-type="bibr">16</xref>
] NSP9 – a RNA-binding protein, the dimeric form of which is important for viral infection. Induction of disturbance to the dimerization of NSP9[<xref rid="ref19" ref-type="bibr">19</xref>
] can be a way to overcome CoV infection.[<xref rid="ref20" ref-type="bibr">20</xref>
] NSP10 acts as a cofactor for the activation of the replicative enzyme.[<xref rid="ref21" ref-type="bibr">21</xref>
] NSP12 shows RNA-dependent RNA polymerase activity, NSP13 shows helicase activity, NSP14 shows exoribonuclease activity, NSP15 shows endoribonuclease activity, and NSP16 has methyltransferase activity.[<xref rid="ref18" ref-type="bibr">18</xref>
] All NSPs have an important role in replication and transcription.[<xref rid="ref18" ref-type="bibr">18</xref>
]</p>
<p>Synthesized proteins such as M, E, and S are entered into the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) complex and make the structure of viral envelope.[<xref rid="ref22" ref-type="bibr">22</xref>
] On the other hand, the replicated genome binds to N protein and forms the ribonucleoprotein (RNP) complex. The outer cover is formed by the M, E, and S proteins.[<xref rid="ref22" ref-type="bibr">22</xref>
] Finally, the virus particle comes out of the ERGIC by making a bud-like structure.[<xref rid="ref23" ref-type="bibr">23</xref>
] These mature virions form a vesicle, which fuses with the plasma membrane and releases the virus particles into the extracellular region.[<xref rid="ref23" ref-type="bibr">23</xref>
<xref rid="ref24" ref-type="bibr">24</xref>
] The detailed structure of CoV and its life cycle is depicted in Figures <xref ref-type="fig" rid="F1">1</xref>
and <xref ref-type="fig" rid="F2">2</xref>
. On infection, the SARS-CoV and MERS-COV cause a surge of pro-inflammatory cytokines and chemokines, which cause damage to lung tissue,[<xref rid="ref13" ref-type="bibr">13</xref>
] deterioration of lung function, and then finally lung failure in some cases.[<xref rid="ref25" ref-type="bibr">25</xref>
]</p>
<fig id="F1" position="float"><label>Figure 1</label>
<caption><p>Structural details of Coronavirus</p>
</caption>
<graphic xlink:href="IJPharm-52-56-g001"></graphic>
</fig>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p>The life cycle of CoV in host cells. The S proteins of CoV binds to cellular receptor angiotensin-converting enzyme 2 (ACE2) which is followed by entry of the viral RNA genome into the host cell and translation of structural and non structural proteins (NSP) follows. ORF1a and ORF1ab are translated to produce pp1a and pp1ab polyproteins, which are cleaved by the proteases that are encoded by ORF1a to yield 16 non-structural proteins. This is followed by assembly and budding into the lumen of the ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment). Virions are then released from the infected cell through exocytosis. S: spike, E: envelope, M: membrane, N: nucleocapsid. PP: polyproteins, ORF: Open reading frame, CoV: coronavirus</p>
</caption>
<graphic xlink:href="IJPharm-52-56-g002"></graphic>
</fig>
<p>Currently, there is no specific antiviral drug for the treatment of CoV-associated pathologies. Most treatment strategies focus on symptomatic management and supportive therapy only.[<xref rid="ref26" ref-type="bibr">26</xref>
<xref rid="ref27" ref-type="bibr">27</xref>
] Some therapeutic agents that are under development or being used off-label are ribavirin, interferon (IFN)-α, and mycophenolic acid.[<xref rid="ref7" ref-type="bibr">7</xref>
] There are many newspaper articles citing effectiveness of anti-HIV drugs: ritonavir,[<xref rid="ref28" ref-type="bibr">28</xref>
<xref rid="ref29" ref-type="bibr">29</xref>
] lopinavir,[<xref rid="ref29" ref-type="bibr">29</xref>
] either alone or in combination with oseltamivir,[<xref rid="ref29" ref-type="bibr">29</xref>
] remdesivir, and chloroquine;[<xref rid="ref28" ref-type="bibr">28</xref>
] and among these, ritonavir, remdesivir, and chloroquine showed efficacy at cellular level[<xref rid="ref28" ref-type="bibr">28</xref>
] which further need experimental support and validation.</p>
<p>As there is no well-defined therapy available, which specifically targets CoV, in this article, we have reviewed the possible protein structures, which could be potential targets for the development of a therapeutic approach for the treatment of CoV.</p>
</sec>
<sec sec-type="materials|methods" id="sec1-3"><title>Materials and Methods</title>
<sec id="sec2-1"><title>Database screen</title>
<p>We screened PubMed and RCSB database with the keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The database files were extracted using endnote, and title and abstract screening was done using Rayyan QCRI. Full texts of these screened articles were further screened for possible inclusion in the systematic review. Articles that evaluated different druggable targets of CoV and evaluated different therapeutic measures against some identifiable target were included for further review.</p>
</sec>
</sec>
<sec sec-type="results|discussion" id="sec1-4"><title>Results and Discussion</title>
<p>A total of 392 articles were found after preliminary screening of the databases. After title and abstract screening, a total of 230 articles were excluded. Full-text screening of the remaining 154 articles was done. Among these studies, after full-text screening, a total of 122 articles were included in the final review. The PRISMA flowchart of the study is shown in <xref ref-type="fig" rid="F3">Figure 3</xref>
. Thirty-two articles were excluded after full-text screen (review articles = 7, articles not specifying drug targets against CoV = 22, articles in other language other than English = 3). Details of studies with important structural and functional target proteins are summarized in <xref rid="T1" ref-type="table">Table 1</xref>
.</p>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><p>Flowchart</p>
</caption>
<graphic xlink:href="IJPharm-52-56-g003"></graphic>
</fig>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Details of studies representing protein database structures of major targets in coronavirus and their structures</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">PDB ID</th>
<th align="left" rowspan="1" colspan="1">Details</th>
<th align="left" rowspan="1" colspan="1">Inhibitor</th>
<th align="center" rowspan="1" colspan="1">IC<sub>50</sub>
</th>
<th align="center" rowspan="1" colspan="1">Reference</th>
</tr>
<tr><th align="left" colspan="5" rowspan="1"><hr></hr>
</th>
</tr>
<tr><td align="center" colspan="5" rowspan="1">N protein</td>
</tr>
</thead>
<tbody><tr><td align="left" rowspan="1" colspan="1">4KXJ</td>
<td align="left" rowspan="1" colspan="1">Interaction between PJ34 and NTD of N protein of HCoV-OC43</td>
<td align="left" rowspan="1" colspan="1">PJ34</td>
<td align="center" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref26" ref-type="bibr">26</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3V3P</td>
<td align="left" rowspan="1" colspan="1">Structure not released</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref30" ref-type="bibr">30</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4LM7</td>
<td align="left" rowspan="1" colspan="1">Interactions of NTD of N protein of HCoV-OC43 with UMP</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref26" ref-type="bibr">26</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4LI4</td>
<td align="left" rowspan="1" colspan="1">Interactions of NTD of N protein of HCoV-OC43 with AMP</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref26" ref-type="bibr">26</xref>
]</td>
</tr>
<tr><td align="left" colspan="5" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="center" colspan="5" rowspan="1"><bold>Protease</bold>
</td>
</tr>
<tr><td align="left" colspan="5" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4TWY</td>
<td align="left" rowspan="1" colspan="1">3CLPro of SARS-CoV with an inhibitor</td>
<td align="left" rowspan="1" colspan="1">3BL</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[27]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4TWW</td>
<td align="left" rowspan="1" colspan="1">3CLPro of SARS-CoV with an inhibitor</td>
<td align="left" rowspan="1" colspan="1">41</td>
<td align="center" rowspan="1" colspan="1">63 µM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref27" ref-type="bibr">27</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4WY3</td>
<td align="left" rowspan="1" colspan="1">3CLPro of SARS-CoV with an inhibitor</td>
<td align="left" rowspan="1" colspan="1">3X5</td>
<td align="center" rowspan="1" colspan="1">240 µM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref27" ref-type="bibr">27</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">4OVZ</td>
<td align="left" rowspan="1" colspan="1">CoV PLPro complexed with inhibitor</td>
<td align="left" rowspan="1" colspan="1">P85</td>
<td align="center" rowspan="1" colspan="1">490 nM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref31" ref-type="bibr">31</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3MJ5</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV PL<sup>Pro</sup>
complexed with inhibitor</td>
<td align="left" rowspan="1" colspan="1">GRM</td>
<td align="center" rowspan="1" colspan="1">320 nM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref32" ref-type="bibr">32</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">2FE8</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV PL<sup>Pro</sup>
</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">[33]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">1UK4</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV 3CL<sup>Pro</sup>
and its interactions with an inhibitor</td>
<td align="left" rowspan="1" colspan="1">Substrate analog hexapeptidyl CMK inhibitor</td>
<td align="left" rowspan="1" colspan="1">IC<sub>50</sub>
ca. 2 mM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref34" ref-type="bibr">34</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">1UJ1, 1UK3, 1UK2</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV M-pro, apo-enzyme at different pH</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref34" ref-type="bibr">34</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3VB6</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV 3CLPro in complex with C6Z</td>
<td align="left" rowspan="1" colspan="1">C6Z</td>
<td align="center" rowspan="1" colspan="1">39 µM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref35" ref-type="bibr">35</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3VB5</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV 3CLPro with C4Z</td>
<td align="left" rowspan="1" colspan="1">C4Z</td>
<td align="center" rowspan="1" colspan="1">1.3-4.6 µM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref35" ref-type="bibr">35</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3TLO</td>
<td align="left" rowspan="1" colspan="1">HCoV-NL63 3CLPro</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref36" ref-type="bibr">36</xref>
<xref rid="ref37" ref-type="bibr">37</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">6LU7</td>
<td align="left" rowspan="1" colspan="1">Main protease of 2019-nCoV and its complex with N3 (inhibitor)</td>
<td align="left" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">-</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref38" ref-type="bibr">38</xref>
]</td>
</tr>
<tr><td align="left" colspan="5" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="center" colspan="5" rowspan="1"><bold>Spike protein</bold>
</td>
</tr>
<tr><td align="left" colspan="5" rowspan="1"><hr></hr>
</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">5ZUV</td>
<td align="left" rowspan="1" colspan="1">HR1 motif of HCoV-229E in complex with EK1</td>
<td align="left" rowspan="1" colspan="1">Modified OC43-HR2P peptide (EK1)</td>
<td align="center" rowspan="1" colspan="1">0.19-0.62 µM</td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref39" ref-type="bibr">39</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">5ZVM</td>
<td align="left" rowspan="1" colspan="1">EK1 in complex with SARS HR1 motif</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref39" ref-type="bibr">39</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">5X4S</td>
<td align="left" rowspan="1" colspan="1">NTD of SARS-CoV S protein</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref40" ref-type="bibr">40</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">5WRG</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV S protein</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref41" ref-type="bibr">41</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">6Q05</td>
<td align="left" rowspan="1" colspan="1">MERS-CoV S structure in complex with Sialyl-Lewis</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref42" ref-type="bibr">42</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">6ACG</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV S protein: ACE-2 (conformation 1) complex</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref43" ref-type="bibr">43</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">6ACK</td>
<td align="left" rowspan="1" colspan="1">SARS-CoV S protein: ACE-2 (conformation 3) complex</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref43" ref-type="bibr">43</xref>
]</td>
</tr>
<tr><td align="left" rowspan="1" colspan="1">3SCI</td>
<td align="left" rowspan="1" colspan="1">RBD of S protein interaction with ACE-2</td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1"></td>
<td align="center" rowspan="1" colspan="1">[<xref rid="ref44" ref-type="bibr">44</xref>
] to be published</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>NTD=N-terminal domain, CoV=Coronovirus, 3CLPro=3C-like protease, PL<sup>pro</sup>
=Papain-like protease, MERS=Middle East respiratory syndrome, SARS=Severe acute respiratory syndrome, ACE-2=Angiotensin converting enzyme-2, RBD=Receptor-binding domain, nCoV=Novel coronavirus, S protein=Spike protein</p>
</fn>
</table-wrap-foot>
</table-wrap>
<sec id="sec2-2"><title>Spike protein</title>
<p>The spike protein is a clove-shaped, type I-TM protein.[<xref rid="ref2" ref-type="bibr">2</xref>
] The spike protein has three segments that are ectodomain (ED) region, TM region, and intracellular domain, which comprises the intracellular short tail part.[<xref rid="ref2" ref-type="bibr">2</xref>
] The receptor-binding S1 domain (three S1 heads) and the membrane fusion subunit S2 (trimeric stalk) on C-terminal together comprise the ED. Spike proteins gather in the trimeric form on the outer surface of the virion, giving it the appearance of a crown, due to which it is called CoV.[<xref rid="ref2" ref-type="bibr">2</xref>
] The spike protein plays an important role in virus entry into the host.[<xref rid="ref10" ref-type="bibr">10</xref>
] Initial interactions between the S1 domain and its host receptor (ACE2 in case of SARS-CoV and PP 4 In case of MERS-CoV) and subsequent S2 segment mediated fusion of the host and viral membranes allow the CoV- RNA genome to enter inside the host cells and thus, these proteins represent as important targets from drug discovery side.[<xref rid="ref10" ref-type="bibr">10</xref>
] The spike protein also activates the immune response of the host cell toward CoV.[<xref rid="ref10" ref-type="bibr">10</xref>
]</p>
<sec id="sec3-1"><title>S1 domain</title>
<p>The main components of the S1 domain are the N-terminal domain (NTD) and the C-terminal domain (CTD). The S1 domain acts as a major antigen on the surface of the virus[<xref rid="ref40" ref-type="bibr">40</xref>
] and has a receptor-binding domain (RBD).[<xref rid="ref25" ref-type="bibr">25</xref>
] The 18 residues of ACE-2 interact with the RBD (contain 14 amino acids) of SARS-CoV spike protein,[<xref rid="ref45" ref-type="bibr">45</xref>
] and for this contact, K341 of ACE-2 and R453 residue of RBD play the most important role. If point mutated on the D454 or R441 of RBD, it disturbs the binding activity with ACE-2.[<xref rid="ref25" ref-type="bibr">25</xref>
] The S1 domain interacts with the ACE-2 or DPP-4 receptors of the host. Anti-ACE-2 antibody blocked viral entry and replication in Vero E6 cells.[<xref rid="ref14" ref-type="bibr">14</xref>
<xref rid="ref45" ref-type="bibr">45</xref>
] One another mechanism of virus for binding to host cell is using dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN receptor) or L-SIGN in lymph nodes or in liver.[<xref rid="ref46" ref-type="bibr">46</xref>
<xref rid="ref47" ref-type="bibr">47</xref>
] S protein has seven (109, 118, 119, 158, 227, 589, and 699) glycosylation asparagine-linked sites, which is pivotal for both L-SIGN- or DC-SIGN-based virus entry into the host.[<xref rid="ref48" ref-type="bibr">48</xref>
]</p>
</sec>
<sec id="sec3-2"><title>S2 subunit</title>
<p>The S2 subunit has two heptad repeat regions (HR 1 and 2) and hydrophobic fusion peptide.[<xref rid="ref25" ref-type="bibr">25</xref>
]</p>
</sec>
<sec id="sec3-3"><title>Drug designing strategies targeting S protein and its interactions</title>
<p>The RBD is targeted in many drug designing studies.[<xref rid="ref25" ref-type="bibr">25</xref>
] A peptide sequence with sequence similarity to the RBD of S protein hampered S1-RBD: ACE-2 interaction and prevented entry of SARS-CoV into Vero cells (IC<sub>50</sub>
around 40 μM).[<xref rid="ref25" ref-type="bibr">25</xref>
<xref rid="ref49" ref-type="bibr">49</xref>
<xref rid="ref50" ref-type="bibr">50</xref>
]</p>
<p>A SARS-CoV RBD-specific antibody (FM6) failed to inhibit the occurrence of infection.[<xref rid="ref39" ref-type="bibr">39</xref>
]</p>
<p>OC43-HR2P, a peptide derived from heptad repeat 2 regions of S2 domain of HCoV-OC43 and its optimized form EK1, showed pan-CoV fusion inhibition property.[<xref rid="ref39" ref-type="bibr">39</xref>
] The structure (protein data bank [PDB] ID 5ZUV and 5ZVM) shows a stable 6-helix bundle structure with α-HCoV and long β-HCoV-HR1 domain.[<xref rid="ref39" ref-type="bibr">39</xref>
]</p>
<p>Chloroquine, an antimalarial agent, inhibits SERS-CoV by elevation of endosomal pH and alters the terminal glycosylation of ACE-2, which ultimately interferes with the virus receptor binding.[<xref rid="ref51" ref-type="bibr">51</xref>
]</p>
<p>Other inhibitors SSAA09E2 block the S-ACE2 interaction, SSAA09E1 inhibits the host protease cathepsin L (which is important for viral entry), and SSAA09E3 prevents fusion of host and viral cell membrane.[<xref rid="ref52" ref-type="bibr">52</xref>
]</p>
<p>Kao <italic>et al</italic>
. identified 18 small molecules that targeted the S-ACE-2-mediated entry of virus into human cell.[<xref rid="ref53" ref-type="bibr">53</xref>
] In 293T cells expressing ACE-2, one of these agents (VE607) showed a significant inhibition of SARS-pseudovirus entry.[<xref rid="ref53" ref-type="bibr">53</xref>
] In Vero E6 cells, two other molecules tetra-O-galloyl beta-D-glucose and luteolin also inhibited SARS-pseudovirus and SARS-CoV infection.[<xref rid="ref53" ref-type="bibr">53</xref>
] In virus-infected Vero E6 cells, a siRNA against the S sequences of SARS-CoV inhibited SARS-CoV replication.[<xref rid="ref25" ref-type="bibr">25</xref>
<xref rid="ref54" ref-type="bibr">54</xref>
]</p>
<p>The S230 antibody (origin: memory B-cells of SARS-CoV-infected persons) neutralizes wide spectrum of isolates of SARS-CoV.[<xref rid="ref55" ref-type="bibr">55</xref>
] S230 antibody Fab fragment binds to the SARS-CoV complex to neutralize it, and their structures are also available (PDB IDs: 6NB6, 6NB7, and 6NB8.[<xref rid="ref55" ref-type="bibr">55</xref>
] The monoclonal antibody, m396, has a competitive role for RBD binding (PDB ID: 2DD8).[<xref rid="ref56" ref-type="bibr">56</xref>
]</p>
<p>Monoclonal antibody can be generated by immunizing the spike protein of SERS-CoV (transgenic mice) or from the B-cells of CoV-infected persons.[<xref rid="ref25" ref-type="bibr">25</xref>
] Spike-specific monoclonal antibodies 80R and CR301 block the S-ACE-2 interactions and thus neutralize infection by human SARS-CoV (HKu39849 and Tor2) and palm civet strain (SZ3).[<xref rid="ref25" ref-type="bibr">25</xref>
]</p>
<p>Mice vaccinated with SARS-n DNA showed T-cell immune response (both induction and proliferation),[<xref rid="ref57" ref-type="bibr">57</xref>
] and cytotoxic T-cell response was seen against SARS-DNA-transfected alveolar epithelial cells.</p>
</sec>
</sec>
<sec id="sec2-3"><title>Envelop protein (E)</title>
<p>The E protein is the smallest (8.4–12 kDa size) TM structural protein of CoV.[<xref rid="ref58" ref-type="bibr">58</xref>
<xref rid="ref59" ref-type="bibr">59</xref>
] Two distinct domains comprise the E protein: the hydrophobic domain and the charged cytoplasmic tail. However, the structure is highly variable among different members of the CoV family.[<xref rid="ref59" ref-type="bibr">59</xref>
]</p>
<p>The E protein has a special role in viral morphogenesis, especially during assembly and egress.[<xref rid="ref59" ref-type="bibr">59</xref>
] CoVs lacking E protein show lower viral titer, immature, and inefficient progenies.[<xref rid="ref58" ref-type="bibr">58</xref>
<xref rid="ref60" ref-type="bibr">60</xref>
] Oligomerization of E proteins leads to the formation of ion channels.[<xref rid="ref61" ref-type="bibr">61</xref>
] However, the importance of these ion channels is still not clear. Many other studies infer that the E protein acts in coordination with other intracellular proteins and modulates the activity of those proteins.[<xref rid="ref59" ref-type="bibr">59</xref>
] E protein also acts as a virulence factor.[<xref rid="ref59" ref-type="bibr">59</xref>
] E protein has an important role in CoV assembly and budding formation.[<xref rid="ref24" ref-type="bibr">24</xref>
] Apart from this, E protein found around the ER and Golgi body regions.[<xref rid="ref60" ref-type="bibr">60</xref>
] Hexamethylene amiloride blocks this E protein-associated ion channel activity in the mammalian cells expressing SERS-CoV envelop protein.[<xref rid="ref62" ref-type="bibr">62</xref>
]</p>
</sec>
<sec id="sec2-4"><title>Membrane protein</title>
<p>Maintenance of the shape of the viral envelope is the most important function of the M protein,[<xref rid="ref60" ref-type="bibr">60</xref>
] and the M protein performs this job by interacting with other CoV proteins,[<xref rid="ref63" ref-type="bibr">63</xref>
] incorporation of Golgi complex into new virions,[<xref rid="ref60" ref-type="bibr">60</xref>
] and stabilization of nucleocapsid protein.[<xref rid="ref60" ref-type="bibr">60</xref>
]</p>
<p>The M protein is characterized by three TM domains[<xref rid="ref64" ref-type="bibr">64</xref>
] with C-terminal inside (long) and N-terminal (short) outside.[<xref rid="ref63" ref-type="bibr">63</xref>
] The details of the protein structure is available in UniProt.[<xref rid="ref65" ref-type="bibr">65</xref>
] Through multiple protein–protein interactions, the M protein plays a crucial role in viral intracellular homeostasis.[<xref rid="ref60" ref-type="bibr">60</xref>
] Interaction between M–M, M–S, and M–N proteins takes a special part in viral assembly.[<xref rid="ref60" ref-type="bibr">60</xref>
] The M–S interactions are necessary for the interaction of spike protein in the ERGIC complex, also known as the Golgi complex, which is later incorporated into new viral progenies.[<xref rid="ref60" ref-type="bibr">60</xref>
] The M–N interactions are crucial for the stabilization of the RNP complex (nucleocapsid–RNA complex), which forms the viral core.[<xref rid="ref60" ref-type="bibr">60</xref>
] The M protein and the N protein are the major viral envelope proteins, defining viral shape, but it also takes part in the formation and release of virus-like particles.[<xref rid="ref60" ref-type="bibr">60</xref>
]</p>
<p>M protein also takes part in the sensitization of the host by the virus.[<xref rid="ref66" ref-type="bibr">66</xref>
] The M protein of SARS-CoV activates the nuclear factor kappa pathway and IFN-beta pathway, through a Toll-like receptor-dependent mechanism. Again, a mutated M protein (V-68) failed to illicit an IFN-beta response.[<xref rid="ref66" ref-type="bibr">66</xref>
]</p>
<p>Mice vaccinated with SARS-M DNA showed T-cell immune response (both induction and proliferation),[<xref rid="ref57" ref-type="bibr">57</xref>
] and cytotoxic T-cell response was seen against SARS-DNA-transfected alveolar epithelial cells.</p>
</sec>
<sec id="sec2-5"><title>Nucleocapsid protein (N)</title>
<p>The structure of nucleocapsid protein (N protein) is conserved across different members of the CoV family. The three characteristic intrinsically disordered regions (IDRs) of the nucleocapsid (N) protein are the N-arm, central linker (CL), and the C-tail.[<xref rid="ref4" ref-type="bibr">4</xref>
] The NTD and the CTD are the major structural and functional domain of the nucleocapsid protein. The most important function of the N protein NTD is RNA binding, while the primary job of the CTD is dimerization.[<xref rid="ref4" ref-type="bibr">4</xref>
<xref rid="ref9" ref-type="bibr">9</xref>
] As the CL region is rich in arginine and serine residue content, it also contains a large number of phosphorylation sites.[<xref rid="ref26" ref-type="bibr">26</xref>
] The C-terminal IDRs take an important part in nucleocapsid protein oligomerization and N–M protein interactions.[<xref rid="ref67" ref-type="bibr">67</xref>
]</p>
<p>Formation and maintenance of the RNP complex are the most important functions of the N protein.[<xref rid="ref9" ref-type="bibr">9</xref>
] It also regulates the replication and transcription of viral RNA, and in the host, it inhibits protein translation through EF1α-mediated action,[<xref rid="ref9" ref-type="bibr">9</xref>
] alteration of host cell metabolism, host cell cycle (N proteins are reported to inhibit CDK4), and apoptosis.[<xref rid="ref3" ref-type="bibr">3</xref>
<xref rid="ref9" ref-type="bibr">9</xref>
] In human peripheral blood, N protein inhibits cell proliferation through the inhibition of cytokinesis.[<xref rid="ref68" ref-type="bibr">68</xref>
]</p>
<p>The NTD contains sites for RNA binding. The RNA-binding sites on the NTD of N protein were identified by observing its interactions with ribonucleoside 5'-monophosphates (AMP, UMP, CMP, and GMP).[<xref rid="ref26" ref-type="bibr">26</xref>
] Using the information about interaction between AMP and UMP binding to the NTD of nucleocapsid protein, inhibitors of RNA binding were designed. Three-dimensional structure with all complex can see from PDB that is 4LMC, 4LM9, 4LM7, and 4LI4, respectively.[<xref rid="ref26" ref-type="bibr">26</xref>
] One such molecule which was designed with this strategy is N-(6-oxo-5,6-dihydrophenanthridine-2-yl) (N, N dimethyl amino) (PJ34), which was designed using the HCoV-OC43 model.[<xref rid="ref26" ref-type="bibr">26</xref>
] Binding of PJ34 on NTD affects the genome binding and replication process of CoV.[<xref rid="ref26" ref-type="bibr">26</xref>
] The crystal structure of COV-OC43 N-NTD with inhibitor PJ34 complex is given in PDB ID: 4KXJ.[<xref rid="ref26" ref-type="bibr">26</xref>
] On the basis of interactions between PJ34 and NTD of nucleocapsid protein, another inhibitor was designed that is H3 (6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-5,8-dione), which also inhibits RNA binding.[<xref rid="ref26" ref-type="bibr">26</xref>
<xref rid="ref69" ref-type="bibr">69</xref>
] This highlights the importance of NTD in RNA binding. Some of the herbal products, such as catechin gallate and gallocatechin gallate (both are polyphenolic compounds), have shown the inhibitory action against SARS-CoV.[<xref rid="ref70" ref-type="bibr">70</xref>
]</p>
<p>The CTD of N protein has a primary role in oligomerization, especially the C-terminal end. A C-terminal tail peptide sequence N377–389 competes with the oligomerization process and significant inhibition of viral titer was seen at 300 μM concentration.[<xref rid="ref71" ref-type="bibr">71</xref>
]</p>
<p>N220, which is a nucleocapsid protein peptide, showed a high binding affinity to human MHC-1 in T2 cells, and the peptide sequence was successful in activating T-cells (cytotoxic). In transgenic animals, the peptide further showed potential to selective killing of nucleocapsid protein expressing cells and is a potential candidate for DNA vaccine.[<xref rid="ref72" ref-type="bibr">72</xref>
] Other N protein-targeted peptides of importance are NP111, NP331, and NP351.[<xref rid="ref72" ref-type="bibr">72</xref>
<xref rid="ref73" ref-type="bibr">73</xref>
]</p>
</sec>
<sec id="sec2-6"><title>Proteases</title>
<p>The SERS-CoV genome encodes a number of proteins. The replicase gene, which is a major component of the CoV genome encoded for 16 NSPs in the form of two large PPs (PP1a and PP1ab).[<xref rid="ref74" ref-type="bibr">74</xref>
] Two types of cysteine proteases act on these PPs to release the NSPs. The C-terminal end of these PPs is cleaved by chymotrypsin-like cysteine protease (main protease [M<sup>pro</sup>
] or 3C-like protease [3CLpro]) and the N-terminal end is processed by the M<sup>pro</sup>
(also known as papain-like protease [PL<sup>pro</sup>
]).[<xref rid="ref74" ref-type="bibr">74</xref>
] The first three cleavage sites of the PPs is cut by PL<sup>pro</sup>
while the rest 11 sites are cleaved by CLpro, and this cleavage results in release of 16 NSPs.[<xref rid="ref75" ref-type="bibr">75</xref>
]</p>
<sec id="sec3-4"><title>3C-like protease</title>
<p>The 3CLpro is present in homodimer form and has cys-his dyad on active site which shows protease activity.[<xref rid="ref27" ref-type="bibr">27</xref>
] If mutated on the Ser139 and phe140 positions, it abolishes the dimerization of 3CLPro (PDB ID: 3F9G).[<xref rid="ref76" ref-type="bibr">76</xref>
] This protease can cleave 11 sites in the p1 position of PP1a and PP1ab and can produce a mature protein that anchors the replication/transcription complex[<xref rid="ref3" ref-type="bibr">3</xref>
<xref rid="ref77" ref-type="bibr">77</xref>
] and also releases the mature NSPs.[<xref rid="ref78" ref-type="bibr">78</xref>
]</p>
<p>N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl) acetamido) phenyl) carboxamides are also found to be important inhibitors of CLPro. The structure of CLPro inhibitor is with ML188 (IC50 1.5 μM) is reported (CID: 46897844, PDB ID: 3V3M).[<xref rid="ref79" ref-type="bibr">79</xref>
<xref rid="ref80" ref-type="bibr">80</xref>
] Another structure with CLPro inhibitor ML300 (PDB ID: 4MDS, IC<sub>50</sub>
: 6.2 μM) is reported.[<xref rid="ref79" ref-type="bibr">79</xref>
] Some metal-conjugated and peptidomimetic compounds showed inhibitory activity against 3CLpro.[<xref rid="ref77" ref-type="bibr">77</xref>
] Some of the small molecules also act as an inhibitor that is arylboronic acids, quinolinecarboxylate derivatives, thiophenecarboxylate, and phthalhydrazide-substituted ketoglutamine analogs.[<xref rid="ref77" ref-type="bibr">77</xref>
] Some flavonoids are also reported to inhibit M<sup>pro</sup>
.[<xref rid="ref75" ref-type="bibr">75</xref>
] GC376 also has protease inhibitor activity.[<xref rid="ref81" ref-type="bibr">81</xref>
] A crystal structure of M<sup>pro</sup>
with small molecule inhibitor N3 is also reported (PDB ID: 2AMQ).[<xref rid="ref82" ref-type="bibr">82</xref>
] Lopinavir and ritonavir, which are the inhibitors of HIV protease, also inhibit M<sup>pro</sup>
.[<xref rid="ref83" ref-type="bibr">83</xref>
] <italic>In silico</italic>
studies directed that among commercially available drugs, colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprostenol, vapreotide, aprepitant, caspofungin, and perphenazine also bind to the lopinavir/ritonavir-binding site on CoV.[<xref rid="ref83" ref-type="bibr">83</xref>
]</p>
</sec>
</sec>
<sec id="sec2-7"><title>Papain-like protease</title>
<p>The PL<sup>pro</sup>
cleaves the N-terminal region of the PP to generate three NSPs (NSP 1, 2, and 3).[<xref rid="ref3" ref-type="bibr">3</xref>
<xref rid="ref74" ref-type="bibr">74</xref>
] PL<sup>pro</sup>
has a catalytic core domain that contains 316 amino acid, which is responsible for cleaving replicase substrates, and a consensus sequence LXGG was required for cleavage.[<xref rid="ref78" ref-type="bibr">78</xref>
] Higher doses of zinc and zinc conjugates were found to inhibit both types of SARS protease (CLpro and PLpro).[<xref rid="ref84" ref-type="bibr">84</xref>
] Benzodioxole can inhibit the PL<sup>pro</sup>
enzyme. The crystal structure of interaction is shown in PDB ID: 4OVZ, 4OWZ.[<xref rid="ref31" ref-type="bibr">31</xref>
] Through <italic>in silico</italic>
approach, another new lead was identified (6577871) which was further optimized, and compound 15h (S configuration, enzyme IC<sub>50</sub>
=0.56 μM, antiviral EC<sub>50</sub>
=9.1 μM) and 15g (R configuration, enzyme IC<sub>50</sub>
=0.32 μM; antiviral EC<sub>50</sub>
=9.1 μM) were found to be the most important inhibitors.[<xref rid="ref32" ref-type="bibr">32</xref>
] The crystallized structural details of these interactions can be visualized in the PDB database (PDB ID: 2FE8 and 3E9S).[<xref rid="ref32" ref-type="bibr">32</xref>
]</p>
<p>Many of the protease inhibitors are being used in the treatment of COVID-19, e.g., lopinavir–ritonavir combinations.[<xref rid="ref85" ref-type="bibr">85</xref>
]</p>
</sec>
<sec id="sec2-8"><title>Hemagglutinin esterase</title>
<p>This HE enzyme is present in the envelope of CoV, more specifically among beta-coronaviridiae.[<xref rid="ref86" ref-type="bibr">86</xref>
] The HE is a marker of CoV and influenza virus evolution.[<xref rid="ref86" ref-type="bibr">86</xref>
] HE mediates reversible attachment to O-acetylated-sialic-acids by acting both as lectins and as receptor-destroying enzymes.[<xref rid="ref86" ref-type="bibr">86</xref>
] Interactions between HE in complex with sialic acid can be visualized in PDB ID: 3CL5.[<xref rid="ref86" ref-type="bibr">86</xref>
]</p>
</sec>
<sec id="sec2-9"><title>NTPase/helicase</title>
<p>NTPase/helicase plays an important role in the central dogma of the virus.[<xref rid="ref87" ref-type="bibr">87</xref>
] SARS-CoV helicase enzyme is a member of the SF1. This enzyme prefers ATP, dATP, and dCTP as substrates; it also hydrolyzed all NTPs.[<xref rid="ref88" ref-type="bibr">88</xref>
] Toxicity issues are main obstacles in the development of inhibitors of helicase, and nonspecificity of inhibitors may cause serious toxicity.[<xref rid="ref87" ref-type="bibr">87</xref>
] However, despite theoretical limitations, helicase is being increasingly recognized as a druggable target for different disease conditions.[<xref rid="ref89" ref-type="bibr">89</xref>
]</p>
</sec>
</sec>
<sec id="sec1-5"><title>Other Strategies to Counter Coronavirus: Endosomal pH</title>
<p>Once entered into the host cell, the subsequent life cycle of SERS-CoV requires low pH.[<xref rid="ref90" ref-type="bibr">90</xref>
] Inhibitors of pH-sensitive endosomal protease block CoV infection.[<xref rid="ref90" ref-type="bibr">90</xref>
<xref rid="ref91" ref-type="bibr">91</xref>
] Several different small compounds and molecules have been reported against virus infection. Amiodarone gets accumulated in the acidic organelles. Vacuoles on exposure to amiodarone shows alteration in intracellular organelles especially enlargement of late endosomes. In <italic>in-vitro</italic>
environment, amiodarone inhibited coronavirus infection in Vero cells.[<xref rid="ref92" ref-type="bibr">92</xref>
] At priori trypsin, cleavage of S protein is essential for a successful viral entry. However, trypsin cleavage also does not affect the efficacy of amiodarone.[<xref rid="ref92" ref-type="bibr">92</xref>
]</p>
</sec>
<sec id="sec1-6"><title>2019-Novel Coronavirus: Challenges</title>
<p>In the RCSB database, only one PDB (PDB ID: 6LU7) is there on the 2019-nCoV which is in complex with N3 (inhibitor). The complete sequence of the 2019-nCoV is available.[<xref rid="ref93" ref-type="bibr">93</xref>
] However, it is only 95% similar to bat-SL-CoVZC45 and 88% to SIRS CoV-ZSc (nucleotide blast, NCBI). This highlights the amount of recombination processes or changes that occurred in the 2019-nCoV and changes in protein structural and functional levels.</p>
</sec>
<sec id="sec1-7"><title>Clinical Trial Update on 2019-nCoV</title>
<p>A total of 233 trials are registered till date in the Chinese Clinical Trial Registry[<xref rid="ref94" ref-type="bibr">94</xref>
] (dated Feb 24, 2020, keywords 2019-nCov and COVID-19). Among the pharmacotherapeutic agents evaluated, some of the highlighted agents, which are being evaluated, are high-dose Vitamin C, favipiravir, adalimumab, dihydro-artemisinin piperaquine, leflunomide, dipyridamole, chloroquine or hydroxychloroquine, suramin sodium, lopinavir/ritonavir and arbidol (umifenovir) tablets, and IFN-alpha 2b. Other important agents being evaluated are Huo-Shen particles, Xiyanping injection, Shen-Fu injection, etc., many of which are from traditional Chinese medicines background. Use of stem cells is also evaluated frequently.[<xref rid="ref94" ref-type="bibr">94</xref>
]</p>
</sec>
<sec sec-type="conclusion" id="sec1-8"><title>Conclusion</title>
<p>Drug discovery against the CoV is a challenging job owing to frequent recombination events. The development of a vaccine is another important aspect. We need more structural biology details and details of the life cycle of the CoV, which can speed up the drug/vaccine development process against CoV. Again, as a preventive measure, strict vigilance of viral changes in different hosts for prediction of an event is important.</p>
<sec id="sec2-10"><title>Financial support and sponsorship</title>
<p>Nil.</p>
</sec>
<sec id="sec2-11" sec-type="COI-statement"><title>Conflicts of interest</title>
<p>There are no conflicts of interest.</p>
</sec>
</sec>
</body>
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