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Serveur d'exploration MERS

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Development of Small-Molecule MERS-CoV Inhibitors

Identifieur interne : 001437 ( Pmc/Corpus ); précédent : 001436; suivant : 001438

Development of Small-Molecule MERS-CoV Inhibitors

Auteurs : Ruiying Liang ; Lili Wang ; Naru Zhang ; Xiaoqian Deng ; Meng Su ; Yudan Su ; Lanfang Hu ; Chen He ; Tianlei Ying ; Shibo Jiang ; Fei Yu

Source :

RBID : PMC:6316138

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) with potential to cause global pandemics remains a threat to the public health, security, and economy. In this review, we focus on advances in the research and development of small-molecule MERS-CoV inhibitors targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.


Url:
DOI: 10.3390/v10120721
PubMed: 30562987
PubMed Central: 6316138

Links to Exploration step

PMC:6316138

Le document en format XML

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<p>Middle East respiratory syndrome coronavirus (MERS-CoV) with potential to cause global pandemics remains a threat to the public health, security, and economy. In this review, we focus on advances in the research and development of small-molecule MERS-CoV inhibitors targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.</p>
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</TEI>
<pmc article-type="review-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Viruses</journal-id>
<journal-id journal-id-type="iso-abbrev">Viruses</journal-id>
<journal-id journal-id-type="publisher-id">viruses</journal-id>
<journal-title-group>
<journal-title>Viruses</journal-title>
</journal-title-group>
<issn pub-type="epub">1999-4915</issn>
<publisher>
<publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">30562987</article-id>
<article-id pub-id-type="pmc">6316138</article-id>
<article-id pub-id-type="doi">10.3390/v10120721</article-id>
<article-id pub-id-type="publisher-id">viruses-10-00721</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Review</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Development of Small-Molecule MERS-CoV Inhibitors</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Liang</surname>
<given-names>Ruiying</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
<xref ref-type="author-notes" rid="fn1-viruses-10-00721">†</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Lili</given-names>
</name>
<xref ref-type="aff" rid="af2-viruses-10-00721">2</xref>
<xref ref-type="author-notes" rid="fn1-viruses-10-00721">†</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Naru</given-names>
</name>
<xref ref-type="aff" rid="af3-viruses-10-00721">3</xref>
<xref ref-type="author-notes" rid="fn1-viruses-10-00721">†</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Deng</surname>
<given-names>Xiaoqian</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Su</surname>
<given-names>Meng</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Su</surname>
<given-names>Yudan</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hu</surname>
<given-names>Lanfang</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>He</surname>
<given-names>Chen</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ying</surname>
<given-names>Tianlei</given-names>
</name>
<xref ref-type="aff" rid="af4-viruses-10-00721">4</xref>
<xref rid="c1-viruses-10-00721" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jiang</surname>
<given-names>Shibo</given-names>
</name>
<xref ref-type="aff" rid="af4-viruses-10-00721">4</xref>
<xref rid="c1-viruses-10-00721" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6332-4326</contrib-id>
<name>
<surname>Yu</surname>
<given-names>Fei</given-names>
</name>
<xref ref-type="aff" rid="af1-viruses-10-00721">1</xref>
<xref rid="c1-viruses-10-00721" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-viruses-10-00721">
<label>1</label>
College of Life and Science, Hebei Agricultural University, Baoding 071001, China;
<email>ruiyingliang@outlook.com</email>
(R.L.);
<email>dengxiaoqian0926@hotmail.com</email>
(X.D.);
<email>sumeng123@hotmail.com</email>
(M.S.);
<email>suyudan123@hotmail.com</email>
(Y.S.);
<email>hlf0519@hotmail.com</email>
(L.H.);
<email>hechen285@hotmail.com</email>
(C.H.)</aff>
<aff id="af2-viruses-10-00721">
<label>2</label>
Research Center of Chinese Jujube, Hebei Agricultural University, Baoding 071001, China;
<email>yywll@hebau.edu.cn</email>
</aff>
<aff id="af3-viruses-10-00721">
<label>3</label>
Department of Clinical Medicine, Faculty of Medicine, Zhejiang University City College, Hangzhou 310015, China;
<email>zhangnr@zucc.edu.cn</email>
</aff>
<aff id="af4-viruses-10-00721">
<label>4</label>
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China</aff>
<author-notes>
<corresp id="c1-viruses-10-00721">
<label>*</label>
Correspondence:
<email>shmyf@hebau.edu.cn</email>
(F.Y.);
<email>shibojiang@fudan.edu.cn</email>
(S.J.);
<email>tlying@fudan.edu.cn</email>
(T.Y.); Tel.: +86-312-7528935 (F.Y.); +86-21-54237673 (S.J.); +86-21-54237761 (T.Y.)</corresp>
<fn id="fn1-viruses-10-00721">
<label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>17</day>
<month>12</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="collection">
<month>12</month>
<year>2018</year>
</pub-date>
<volume>10</volume>
<issue>12</issue>
<elocation-id>721</elocation-id>
<history>
<date date-type="received">
<day>24</day>
<month>11</month>
<year>2018</year>
</date>
<date date-type="accepted">
<day>12</day>
<month>12</month>
<year>2018</year>
</date>
</history>
<permissions>
<copyright-statement>© 2018 by the authors.</copyright-statement>
<copyright-year>2018</copyright-year>
<license license-type="open-access">
<license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) with potential to cause global pandemics remains a threat to the public health, security, and economy. In this review, we focus on advances in the research and development of small-molecule MERS-CoV inhibitors targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.</p>
</abstract>
<kwd-group>
<kwd>MERS-CoV</kwd>
<kwd>mechanism of action</kwd>
<kwd>small-molecule inhibitor</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="sec1-viruses-10-00721">
<title>1. Introduction</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) has posed a serious threat to public health worldwide because it can cause severe respiratory disease in humans with high mortality (about 36%) [
<xref rid="B1-viruses-10-00721" ref-type="bibr">1</xref>
]. As of 27 November 2018, a total of 2266 human MERS-CoV infections with 804 deaths had been reported from 27 countries in the Middle East, North Africa, Europe, Asia, and North America to the World Health Organization (WHO), with 83% reported by the Kingdom of Saudi Arabia (
<xref ref-type="fig" rid="viruses-10-00721-f001">Figure 1</xref>
) (
<uri xlink:href="https://www.who.int/emergencies/mers-cov/en/">https://www.who.int/emergencies/mers-cov/en/</uri>
).</p>
<p>Phylogenetic and sequencing data strongly suggest that MERS-CoV belongs to the C-lineage of the genus betacoronavirus, the first known lineage C betacoronavirus associated with human infections [
<xref rid="B2-viruses-10-00721" ref-type="bibr">2</xref>
]. The clinical features of MERS-CoV infection range from asymptomatic infection to rapidly progressive acute hypoxemic respiratory failure and extrapulmonary organ dysfunction [
<xref rid="B3-viruses-10-00721" ref-type="bibr">3</xref>
,
<xref rid="B4-viruses-10-00721" ref-type="bibr">4</xref>
,
<xref rid="B5-viruses-10-00721" ref-type="bibr">5</xref>
]. At present, no effective vaccine or therapeutics are available for the prevention or treatment of MERS-CoV infection [
<xref rid="B6-viruses-10-00721" ref-type="bibr">6</xref>
,
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
,
<xref rid="B8-viruses-10-00721" ref-type="bibr">8</xref>
]. However, many basic and clinical studies on anti-MERS-CoV agents have been completed or are ongoing. In this review, we focus on current progress in the research and development of small-molecule MERS-CoV inhibitors, either peptides or compounds, targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.</p>
</sec>
<sec id="sec2-viruses-10-00721">
<title>2. MERS-CoV Life Cycle and Potential Targets for the Development of Small-Molecule Inhibitors Against MERS-CoV Infection</title>
<p>MERS-CoV enters host cells through two pathways. The first involves plasma membrane fusion, which relies on spike (S) protein activation by secreted or surface proteases, such as the transmembrane protease serine 2 (TMPRSS2) and the human airway trypsin-like protease (HAT). The second involves endosomal membrane fusion, in which spike protein activation is facilitated by the pH-dependent endosomal protease cathepsin L (CTSL) [
<xref rid="B9-viruses-10-00721" ref-type="bibr">9</xref>
,
<xref rid="B10-viruses-10-00721" ref-type="bibr">10</xref>
]. The spike protein plays a key role in MERS-CoV attachment to host cells and virus-cell membrane fusion [
<xref rid="B11-viruses-10-00721" ref-type="bibr">11</xref>
]. It contains 1353 amino acids within the viral envelope in trimeric state [
<xref rid="B12-viruses-10-00721" ref-type="bibr">12</xref>
]. Spike protein consists of S1 and S2 subunits. The S1 subunit contains the receptor binding domain (RBD), while the S2 subunit contains the fusion peptide (FP), a long heptad repeat 1 domain (HR1) and a short heptad repeat 2 domain (HR2) [
<xref rid="B13-viruses-10-00721" ref-type="bibr">13</xref>
,
<xref rid="B14-viruses-10-00721" ref-type="bibr">14</xref>
]. MERS-CoV enters the host cell by binding the viral particle via the RBD in spike protein to the cellular receptor dipeptidyl peptidase-4 (DPP4) on the surface of the host cell [
<xref rid="B12-viruses-10-00721" ref-type="bibr">12</xref>
,
<xref rid="B15-viruses-10-00721" ref-type="bibr">15</xref>
]. Then, S2 changes its conformation and inserts its FP into the plasma membrane, or the endosomal membrane if the virion is in the endosome. The HR2 binds to the HR1 to form a six-helix bundle (6-HB) fusion core, which brings viral and cell membranes into close apposition for fusion [
<xref rid="B14-viruses-10-00721" ref-type="bibr">14</xref>
,
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
,
<xref rid="B17-viruses-10-00721" ref-type="bibr">17</xref>
]. During this process, RBD, DPP4, HR1, HR2, and the related proteases, e.g., HAT and TMPRSS2, can all serve as targets for the development of MERS-CoV fusion/entry inhibitors.</p>
<p>After MERS-CoV entry into the host’s cells, the positive RNA genome is translated in the cytoplasm. The genome can be translated into two polyproteins: ppla and pplb, which are cleaved into 16 nonstructural proteins by PL
<sub>pro</sub>
(papain-like protease) and 3CL
<sub>pro</sub>
(3-chymotrypsin-like protease). Hence, the proteases that are critically important for MERS-CoV replication can also be considered as targets for developing MERS-CoV replication inhibitors. However, information about the enzymes required for producing more genome copies and subgenomic mRNA for virus replication is limited. Then, the RNA genome and structural proteins are packaged into viral particles in host cells, and the progeny virus particles are finally released from host cells (
<xref ref-type="fig" rid="viruses-10-00721-f002">Figure 2</xref>
). Although these steps can also be used as targets for the development of MERS-CoV maturation-and-release inhibitors, no such inhibitors have been reported so far.</p>
</sec>
<sec id="sec3-viruses-10-00721">
<title>3. Current Small-Molecule Inhibitors Against MERS-CoV Infection and Their Mechanisms of Action</title>
<sec id="sec3dot1-viruses-10-00721">
<title>3.1. MERS-CoV Entry Inhibitors</title>
<p>MERS-CoV S protein plays a key role in mediating virus entry into host target cells. This process includes binding to host receptors, viral fusion, and final entry into host cells. MERS-CoV pseudovirus expressing S protein, which allows for single-cycle infection in cells expressing receptor DPP4, can be used for screening MERS-CoV fusion/entry inhibitors.</p>
<p>HR2P, spanning residues 1251–1286 in the HR2 domain, with low or no toxic effect in vitro, can effectively inhibit MERS-CoV replication by interacting with the HR1 domain to block spike protein-mediated cell–cell fusion and MERS-CoV pseudovirus entry (
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f003">Figure 3</xref>
) [
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
]. To increase its stability, solubility, and anti-MERS-CoV activity, Lu et al. introduced a Glu, Lys, or Arg residue into HR2P, generating a new peptide, HR2P-M2 (
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
). HR2P-M2 was indeed found to be more stable and soluble than HR2P. It blocked fusion core formation between HR1 and HR2 peptides by binding to the viral S protein HR1 domain and inhibiting S protein-mediated membrane fusion with an EC
<sub>50</sub>
of 0.55 µM (
<xref ref-type="fig" rid="viruses-10-00721-f004">Figure 4</xref>
) [
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
,
<xref rid="B23-viruses-10-00721" ref-type="bibr">23</xref>
]. HR2P-M2 is highly effective in inhibiting MERS-CoV infection in both Calu-3 and Vero cells with an EC
<sub>50</sub>
of about 0.6 µM. Intranasal application of HR2P-M2 could significantly reduce the titers of MERS-CoV in the lung of Ad5-hDPP4 (adenovirus serotype-5–human dipeptidyl peptidase 4)-transduced mice [
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
,
<xref rid="B18-viruses-10-00721" ref-type="bibr">18</xref>
]. Furthermore, intranasal administration of HR2P-M2 before viral challenge fully protected hDPP4-transgenic mice from MERS-CoV infection, whereas all untreated mice died 8 days after viral challenge [
<xref rid="B24-viruses-10-00721" ref-type="bibr">24</xref>
]. Furthermore, by combining HR2P-M2 with interferon β, protection was enhanced for Ad5-hDPP4-transduced mice against infection by MERS-CoV strains with or without mutations in the HR1 region of the S protein, with >1000-fold reduction of viral titers in lung [
<xref rid="B18-viruses-10-00721" ref-type="bibr">18</xref>
].</p>
<p>P21S10, the most effective fusion inhibitor of MERS-CoV, can inhibit MERS-CoV pseudovirus infection with an EC
<sub>50</sub>
of about 1 µM in Huh-7 cells and a CC
<sub>50</sub>
of >100 µM in Huh-7 cells by CCK8 (Cell Counting Kit-8) assay (
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
) [
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]. In addition, a series of synthesized stapled peptides, such as P21S10, P21S2, P21S4, P21S5, P21S8, P21S9, P21S8F, P21S8ZF, etc., could effectively inhibit infection by MERS-CoV pseudovirus and its spike protein-mediated cell fusion by blocking helix-mediated NHR (N-terminal heptad repeats) /CHR (C-terminal heptad repeats) interactions with a low EC
<sub>50</sub>
and a high CC
<sub>50</sub>
in Huh-7 cells [
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
].</p>
<p>P9, a short peptide, exhibited potent and broad spectrum antiviral effects against multiple respiratory viruses in vitro and in vivo [
<xref rid="B21-viruses-10-00721" ref-type="bibr">21</xref>
,
<xref rid="B25-viruses-10-00721" ref-type="bibr">25</xref>
]. P9 inhibited MERS-CoV with an EC
<sub>50</sub>
of about 5 µg/mL in Madin-Darby canine kidney (MDCK) cells, obtained by plaque assay, and a CC
<sub>50</sub>
of 380 µg/mL in MDCK cells obtained by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay (
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
) [
<xref rid="B21-viruses-10-00721" ref-type="bibr">21</xref>
].</p>
<p>Lipopeptides are bioactive peptides that replicate the α-helical chain from the viral fusion machinery [
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]. All 12 lipopeptides inhibit cell−cell fusion mediated by MERS-CoV S protein with EC
<sub>50</sub>
values ranging from 0.1 to >10.0 µM in Huh-7 cells (
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
) [
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]. Among these lipopeptides, LLS and IIS were found to be the most potent MERS-CoV fusion inhibitors with EC
<sub>50</sub>
values of 0.24 µM and 0.1 µM, respectively [
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]. Other lipopeptides such as AAS, FFS, YYS, IIY, IIW, IIH, IIQ, IIK, and IIE can also inhibit cell−cell fusion mediated by MERS-CoV S protein with variable EC
<sub>50</sub>
values [
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
].</p>
<p>Three neurotransmitter inhibitors, including chlorpromazine, fluphenazine, and promethazine, were moderate inhibitors of cell–cell fusion with EC
<sub>50</sub>
values of about 23, 15, and 17 µM, respectively (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(5), (45), (46)) [
<xref rid="B26-viruses-10-00721" ref-type="bibr">26</xref>
]. They can also disrupt clathrin-mediated endocytosis to inhibit MERS-CoV [
<xref rid="B26-viruses-10-00721" ref-type="bibr">26</xref>
].</p>
<p>A small-molecule HIV entry inhibitor targeting gp41 ADS-J1 (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(1)) at the concentration of 20 µM could inhibit >90% of MERS-CoV pseudovirus infection in NBL-7 and Huh-7 cells. ADS-J1 could interrupt the interactions between the HR1 and HR2 of MERS-CoV to form the six-helix bundle, thus inhibiting the entry of pseudotyped MERS-CoV with an EC
<sub>50</sub>
of 0.6 µM in the DPP4-expressing cell line and with a CC
<sub>50</sub>
of 26.9 µM in NBL-7 and Huh-7 cells by MTT assay (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) [
<xref rid="B27-viruses-10-00721" ref-type="bibr">27</xref>
].</p>
<p>The elucidation of MERS-CoV interaction with its host cell is critical to the development of antiviral interventions. In order to gain entry into host cells, MERS-CoV not only uses DPP4 as a functional virus receptor, but also utilizes certain cellular proteases, such as TMPRSS2 and members of the cathepsin family, as activators of the S glycoprotein [
<xref rid="B9-viruses-10-00721" ref-type="bibr">9</xref>
]. TMPRSS2 is expressed in epithelial cells of the human respiratory and gastrointestinal tracts [
<xref rid="B28-viruses-10-00721" ref-type="bibr">28</xref>
,
<xref rid="B29-viruses-10-00721" ref-type="bibr">29</xref>
,
<xref rid="B30-viruses-10-00721" ref-type="bibr">30</xref>
,
<xref rid="B31-viruses-10-00721" ref-type="bibr">31</xref>
]. The respective enzymes from host cells are also excellent targets for the identification of small-molecule MERS-CoV inhibitors. The serine protease inhibitor camostat mesylate (camostat) could completely block syncytium formation, but only partially block virus entry into TMPRSS2-expressing Vero cells (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(2)) [
<xref rid="B31-viruses-10-00721" ref-type="bibr">31</xref>
].</p>
<p>K11777, a compound known to inhibit cruzain, a cathepsin-like protease from the protozoan parasite
<italic>Trypanosoma cruzi</italic>
, can inhibit MERS-CoV with an EC
<sub>50</sub>
of 46 nM (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(3)) [
<xref rid="B32-viruses-10-00721" ref-type="bibr">32</xref>
,
<xref rid="B33-viruses-10-00721" ref-type="bibr">33</xref>
].</p>
<p>Chloroquine inhibited MERS-CoV replication and blocked infection at an early step with an EC
<sub>50</sub>
of 3 µM and a CC
<sub>50</sub>
of 58 µM (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(4)) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
]. Chlorpromazine inhibited MERS-CoV replication at both early and post-entry stages with an EC
<sub>50</sub>
of about 5 µM and a CC
<sub>50</sub>
of 21 µM (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(5)) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
]. However, high cytotoxicity narrowed the therapeutic window in both monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
].</p>
<p>Ouabain and bufalin can inhibit MERS-CoV entry by blocking clathrin-mediated endocytosis (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(6), (7)) [
<xref rid="B25-viruses-10-00721" ref-type="bibr">25</xref>
,
<xref rid="B35-viruses-10-00721" ref-type="bibr">35</xref>
]. The addition of small amounts of ouabain (50 nM) or bufalin (10 to 15 nM) inhibited infection with MERS-CoV and VSV (vesicular stomatitis virus) (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
), but only when the drug was added prior to inoculation in Huh-7 cells [
<xref rid="B35-viruses-10-00721" ref-type="bibr">35</xref>
].</p>
<p>Dihydrotanshinone, a lipophilic compound, showed a decimal reduction at 0.5 µg/mL and excellent antiviral effects at ≥2 μg/mL with a reduction in titer from 6.5 Log to 1.8 Log TCID
<sub>50</sub>
/mL by using a pseudovirus expressing MERS-CoV spike protein (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(8)) [
<xref rid="B36-viruses-10-00721" ref-type="bibr">36</xref>
].</p>
<p>During the biosynthesis of MERS-CoV S protein, the furin inhibitor decanoyl-RVKR-chloromethylketone (dec-RVKR-CMK) at 75 µM can lead to a decrease of the 85-kDa cleaved product in MERS-CoV S wt and S2′ mutant (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(9)) [
<xref rid="B37-viruses-10-00721" ref-type="bibr">37</xref>
].</p>
</sec>
<sec id="sec3dot2-viruses-10-00721">
<title>3.2. MERS-CoV Replication Inhibitors</title>
<sec id="sec3dot2dot1-viruses-10-00721">
<title>3.2.1. MERS-CoV Inhibitors Targeting Papain-Like Protease</title>
<p>Papain-like protease is a cysteine protease that uses the thiol group of cysteine as a nucleophile to attack the carbonyl group of the scissile peptide bond [
<xref rid="B38-viruses-10-00721" ref-type="bibr">38</xref>
,
<xref rid="B39-viruses-10-00721" ref-type="bibr">39</xref>
]. The genome of MERS-CoV encodes two polyproteins, ppla and pplb, which are processed by papain-like protease (PL
<sub>pro</sub>
) and 3C-like protease (3CL
<sub>pro</sub>
) [
<xref rid="B40-viruses-10-00721" ref-type="bibr">40</xref>
]. MERS-CoV has only one papain-like protease, as does SARS-CoV, while other coronaviruses have two enzymes [
<xref rid="B41-viruses-10-00721" ref-type="bibr">41</xref>
,
<xref rid="B42-viruses-10-00721" ref-type="bibr">42</xref>
]. MERS-PL
<sub>pro</sub>
is a part of the nonstructural protein nsp3, which includes three domains—namely, ubiquitin-like domain (UBL), a catalytic triad consisting of C1594–H1761–D1776, and the ubiquitin-binding domain (UBD) at the zinc finger—according to the homology model [
<xref rid="B40-viruses-10-00721" ref-type="bibr">40</xref>
,
<xref rid="B43-viruses-10-00721" ref-type="bibr">43</xref>
]. MERS-PL
<sub>pro</sub>
is a multifunctional enzyme with deISGylating and deubiquitinating (DUB) activities [
<xref rid="B43-viruses-10-00721" ref-type="bibr">43</xref>
], but it can also block the interferon regulatory factor 3 (IRF3) pathway [
<xref rid="B43-viruses-10-00721" ref-type="bibr">43</xref>
,
<xref rid="B44-viruses-10-00721" ref-type="bibr">44</xref>
].</p>
<p>Disulfiram, a drug used in alcohol aversion therapy, has been approved by the U.S. Food and Drug Administration (FDA) since 1951 (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(10)). It can inhibit the activity of some enzymes, such as urease [
<xref rid="B45-viruses-10-00721" ref-type="bibr">45</xref>
], methyltransferase [
<xref rid="B46-viruses-10-00721" ref-type="bibr">46</xref>
], and kinase [
<xref rid="B45-viruses-10-00721" ref-type="bibr">45</xref>
], all by reacting with cysteine residues, suggesting broad-spectrum characteristics [
<xref rid="B47-viruses-10-00721" ref-type="bibr">47</xref>
]. Notably, disulfiram also acts as an allosteric inhibitor of MERS-CoV papain-like protease [
<xref rid="B47-viruses-10-00721" ref-type="bibr">47</xref>
]. Multiple inhibition assays also support a kinetic mechanism by which disulfiram, together with 6TG (6-thioguanine) and/or MPA (mycophenolic acid), can synergistically inhibit MERS-CoV papain-like protease [
<xref rid="B47-viruses-10-00721" ref-type="bibr">47</xref>
]. Hence, the recombination of three clinically available drugs could feasibly be used to treat MERS-CoV infection.</p>
</sec>
<sec id="sec3dot2dot2-viruses-10-00721">
<title>3.2.2. MERS-CoV Inhibitors Targeting 3C-Like Protease</title>
<p>The active site of MERS-3CL
<sub>pro</sub>
can be divided into subsites S1–S6 [
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]. Subsite S1 consists of vital catalytic residue Cys145 with His41 to process polyproteins at 11 conserved Gln sites, followed by small amino acids like Ala, Ser, or Gly [
<xref rid="B49-viruses-10-00721" ref-type="bibr">49</xref>
]. Another crucial component of the S1 subsite is the oxyanion hole formed by the interaction of a carboxylate anion of conserved Gln with Gly143, Ser144, and Cys145, which stabilizes the transition state during proteolysis [
<xref rid="B50-viruses-10-00721" ref-type="bibr">50</xref>
,
<xref rid="B51-viruses-10-00721" ref-type="bibr">51</xref>
]. Glu166 at the entrance of the pocket interacts via H-bond with the Nɛ2 of the conserved Gln [
<xref rid="B50-viruses-10-00721" ref-type="bibr">50</xref>
]. The S2 and S4 subsites contain hydrophobic and bulky side chains such as Val, Leu, or Phe. Subsites S5 and S6 are near the surface of the active site and have little participation in substrate binding [
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
].</p>
<p>Polyproteins pp1a and pp1b are processed by 3CL
<sub>pro</sub>
(11 cleavage sites) and PL
<sub>pro</sub>
(3 cleavage sites), resulting in 16 mature nonstructural proteins, including RNA-dependent RNA polymerase (RdRp) and helicase, which play important roles in the transcription and replication of coronaviruses [
<xref rid="B40-viruses-10-00721" ref-type="bibr">40</xref>
,
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
]. Therefore, both proteases are essential for viral replication, making them attractive targets for drug development [
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
].</p>
<p>The analogues of hits of neuraminidase (NA) inhibitors on MERS-CoV 3CL
<sub>pro</sub>
have been synthesized and showed average-to-good inhibition of MERS-3CL
<sub>pro</sub>
. The better one is the compound
<bold>3k</bold>
with an EC
<sub>50</sub>
of 5.8 μM (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(11)) [
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]. Another two are compounds
<bold>3h</bold>
(
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(12)) and
<bold>3i</bold>
(
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(13)) with EC
<sub>50</sub>
values of 7.3 and 7.4 µM, repsectively (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) [
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]. Furthermore, researchers have concluded that pharmacophores phenyl at R3 and carboxylate, either at R1 or R4, are essential for the antiviral activity [
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]. Since the modification of rings A and B is well tolerated, these rings can be further altered to enhance the activity of the compounds. The SARS-CoV 3CL
<sub>pro</sub>
inhibitor CE-5 can block the function of the MERS-CoV 3CL
<sub>pro</sub>
(
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(14)) [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. Treatment with CE-5 inhibited the activity of MERS-CoV 3CL
<sub>pro</sub>
to 30% of that of DMSO-treated cells at a maximum dose of 50 µM [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. The endpoint evaluation of CE-5 indicated an EC
<sub>50</sub>
of ~12.5 µM in cell culture (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
].</p>
<p>Peptidomimetic inhibitors of enterovirus (
<bold>6b</bold>
,
<bold>6c</bold>
, and
<bold>6d</bold>
) inhibit MERS-CoV with EC
<sub>50</sub>
values ranging from 1.7 to 4.7 µM, as shown by enzymatic assay (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(15), (16), (17)) [
<xref rid="B54-viruses-10-00721" ref-type="bibr">54</xref>
]. As shown in
<xref rid="viruses-10-00721-t001" ref-type="table">Table 1</xref>
, compounds
<bold>6b, 6c,</bold>
and
<bold>6d</bold>
efficiently suppressed viral replication with EC
<sub>50</sub>
values of 1.4, 1.2, and 0.6 µM, respectively, after performing a cytopathic inhibition assay using MERS-CoV-infected Huh-7 cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) [
<xref rid="B54-viruses-10-00721" ref-type="bibr">54</xref>
].</p>
<p>GC376, a dipeptidyl transition state 3CL
<sub>pro</sub>
inhibitor, can substantially inhibit the activity of MERS-CoV 3CL
<sub>pro</sub>
with an EC
<sub>50</sub>
of 1.6 µM by fluorescence resonance energy transfer (FRET) assay (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(18)) [
<xref rid="B55-viruses-10-00721" ref-type="bibr">55</xref>
].</p>
<p>GC813 as well as its synthesizing extended compounds
<bold>10a</bold>
and
<bold>10c</bold>
exhibit inhibition for MERS-CoV with EC
<sub>50</sub>
values of 0.5 µM, 0.5 µM, and 0.8 µM in cell culture (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(18), (19), (20), (21)) [
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
].</p>
<p>N3, a broad-spectrum anti-CoV inhibitor, can inhibit the proteolytic activity of MERS-CoV 3CL
<sub>pro</sub>
by binding with the interface of domain I and II of MERS-CoV 3CL
<sub>pro</sub>
with an EC
<sub>50</sub>
of about 0.3 µM (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(22)) [
<xref rid="B56-viruses-10-00721" ref-type="bibr">56</xref>
].</p>
</sec>
</sec>
<sec id="sec3dot3-viruses-10-00721">
<title>3.3. Other Small-Molecule Inhibitors with Defined or Undefined Mechanisms of Action</title>
<p>Silvestrol, an eIF4A inhibitor, can inhibit MERS-CoV infection with an EC
<sub>50</sub>
of 1.3 nM, as shown by plaque assay in MRC-5 cells and CC
<sub>50</sub>
of 400 nM by MTT assay in peripheral blood mononuclear cells (PBMCs) (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(23)) [
<xref rid="B57-viruses-10-00721" ref-type="bibr">57</xref>
]. Silvestrol has broad-spectrum antiviral activity via the inhibition of the expression of CoV structural and nonstructural proteins (N, nsp8) and the formation of viral replication/transcription complexes [
<xref rid="B57-viruses-10-00721" ref-type="bibr">57</xref>
].</p>
<p>The combination of interferon-α2b and ribavirin can effectively reduce MERS-CoV replication in vitro and in vivo (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(24)) [
<xref rid="B6-viruses-10-00721" ref-type="bibr">6</xref>
]. Rhesus macaques treated with IFN-α2b and ribavirin 8 h after MERS-CoV infection showed improved clinical parameters with no or very mild radiographic evidence of pneumonia compared with untreated macaques [
<xref rid="B6-viruses-10-00721" ref-type="bibr">6</xref>
]. Moreover, treated macaques showed lower levels of systemic (serum) and local (lung) proinflammatory markers in addition to fewer viral genome copies, distinct gene expression, and less severe histopathological changes in the lungs [
<xref rid="B6-viruses-10-00721" ref-type="bibr">6</xref>
].</p>
<p>GS-5734 (Remdesivir), the monophosphoramidate prodrug of the C-adenosine nucleoside analogue GS-441524, can inhibit the replication of the model β-coronavirus murine hepatitis virus (MHV) and RNA synthesis in wild-type (WT) virus, while an nsp14 ExoN (-) mutant lacking proofreading demonstrated increased susceptibility to GS-5734 (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(25)) [
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]. GS-5734 also inhibits MERS-CoV infection with an EC
<sub>50</sub>
of 0.074 ± 0.023 µM and a CC
<sub>50</sub>
of >10 µM in human amniotic epithelial (HAE) cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) [
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]. Furthermore, GS-5734 acts at the early post-infection stage to decrease viral RNA levels, whereas delaying the addition of GS-5734 until 24 h post-infection resulted in decreased viral titer in HAE cell cultures at 48 and 72 h post-infection [
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]. The nucleotide analogue GS-441524 also inhibits the infection of MERS-CoV with an EC
<sub>50</sub>
of 0.9 µM and a CC
<sub>50</sub>
of >100 µM in HAE cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(26)) [
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]. </p>
<p>Resveratrol was found to significantly inhibit MERS-CoV infection as well as prolong cellular survival after virus infection (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
. (27)) [
<xref rid="B66-viruses-10-00721" ref-type="bibr">66</xref>
]. It was found that resveratrol could reduce RNA levels and infection titers in Vero cells [
<xref rid="B66-viruses-10-00721" ref-type="bibr">66</xref>
]. Although resveratrol has minimal cytotoxicity, even at the high concentration of 250 μM, it can be ignored when compared to the much more severe toxicity of MERS-CoV infection [
<xref rid="B66-viruses-10-00721" ref-type="bibr">66</xref>
].</p>
<p>A series of FDA-approved compounds were screened against MERS-CoV (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
) by cell-based ELISA assay (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(28–56)) [
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]. Pharmaceuticals that inhibit MERS-CoV include neurotransmitter inhibitors, estrogen receptor antagonists, kinase signaling inhibitors, inhibitors of lipid or sterol metabolism, protein processing inhibitors, inhibitors of DNA synthesis/repair, as well as inhibitors of ion transport, cytoskeleton (specifically tubulin), and apoptosis [
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]. Antiparasitics and antibacterials are two classes of pharmaceuticals, the functions of which are not obviously linked to coronaviruses, or viruses in general, but nonetheless show antiviral activity against MERS-CoV.</p>
<p>Nocodazole, targeting the cytoskeleton, specifically interferes with microtubule polymerization. It is an antimitotic drug developed for the treatment of cancer, but it was found to show high activity against MERS-CoV (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(57)) [
<xref rid="B67-viruses-10-00721" ref-type="bibr">67</xref>
,
<xref rid="B68-viruses-10-00721" ref-type="bibr">68</xref>
]. Monensin and salinomycin sodium, two of the nine ion channel inhibitors, have inhibitory activity against MERS-CoV, indicating that MERS-CoV may be susceptible to ionophore activities (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(58), (59)). Chlorpromazine and chloroquine appear to target host factors, rather than viral proteins specifically, and the treatment of viral infections in patients aimed at host factors could reconfigure overt manifestations of viral pathogenesis into a less virulent subclinical infection and lower adverse disease outcome (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(60), (29)) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
,
<xref rid="B69-viruses-10-00721" ref-type="bibr">69</xref>
].</p>
<p>Loperamide, an antidiarrheal opioid receptor agonist that reduces intestinal motility, also inhibits the replication of MERS-CoV at low-micromolar concentrations (3.3–6.3 µM)
<italic>in vitro</italic>
(
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(55)) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
]. Lopinavir, the HIV-1 protease inhibitor, inhibits MERS-CoV replication with an EC
<sub>50</sub>
of 8 µM (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(56)) [
<xref rid="B34-viruses-10-00721" ref-type="bibr">34</xref>
].</p>
<p>SSYA10-001 inhibits MERS-CoV replication with an EC
<sub>50</sub>
of ~25 μM in Vero E6 cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(61)) [
<xref rid="B70-viruses-10-00721" ref-type="bibr">70</xref>
]. Molecular modeling data suggest that SSYA10-001 can be docked with a comparable “Glide” score [
<xref rid="B70-viruses-10-00721" ref-type="bibr">70</xref>
].</p>
<p>ESI-09 can reduce virus yield by inhibiting cAMP signaling in a cell type-independent manner (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(62)) [
<xref rid="B61-viruses-10-00721" ref-type="bibr">61</xref>
]. The concentration of MERS-CoV inhibition by ESI-09 was found with an EC
<sub>50</sub>
of 5 to 10 µM and a CC
<sub>50</sub>
> 50 µM for both Calu-3 and Vero E6 cells by using the lactate dehydrogenase (LDH)-based cytotoxicity assay [
<xref rid="B62-viruses-10-00721" ref-type="bibr">62</xref>
]. In addition, the undetectable cytopathic effect (CPE) and minimal expression of viral antigen indicated that Calu-3 cells treated with ESI-09 were almost fully protected [
<xref rid="B61-viruses-10-00721" ref-type="bibr">61</xref>
].</p>
<p>Mycophenolic acid (MPA) can strongly reduce MERS-CoV replication by inhibiting inosine monophosphate dehydrogenase (IMPDH) and guanine monophosphate synthesis with an EC
<sub>50</sub>
of 2.87 µM by cell-based ELISA in Vero E6 cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(63)) [
<xref rid="B60-viruses-10-00721" ref-type="bibr">60</xref>
].</p>
<p>K22 is a spectrum inhibitor which can inhibit MERS-CoV replication by reducing the formation of double membrane vesicles (DMVs) and by the near-complete inhibition of RNA synthesis (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(64)) [
<xref rid="B25-viruses-10-00721" ref-type="bibr">25</xref>
,
<xref rid="B71-viruses-10-00721" ref-type="bibr">71</xref>
].</p>
<p>BCX4430, an adenosine analogue that acts as a non-obligate RNA chain terminator to inhibit viral RNA polymerase function, can inhibit MERS-CoV infection with EC
<sub>50</sub>
of 68.4 μM in Vero E6 cells by highly charged ions (HCIs)-based analysis and CC
<sub>50</sub>
of >100 μM by neutral-red uptake (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(65)) [
<xref rid="B25-viruses-10-00721" ref-type="bibr">25</xref>
,
<xref rid="B62-viruses-10-00721" ref-type="bibr">62</xref>
].</p>
<p>Fleximer nucleoside analogues of acyclovir are doubly flexible nucleoside analogues based on the acyclic sugar scaffold of acyclovir and the flex-base moiety in fleximers responsible for inhibiting RNA-dependent RNA polymerase (RdRp) [
<xref rid="B25-viruses-10-00721" ref-type="bibr">25</xref>
,
<xref rid="B63-viruses-10-00721" ref-type="bibr">63</xref>
]. The target fleximer analogue 2 can inhibit MERS-CoV infection with EC
<sub>50</sub>
of 27 μM and CC
<sub>50</sub>
of 149 μM in Huh-7 cells, but EC
<sub>50</sub>
of 23 μM and CC
<sub>50</sub>
of 71 μM in Vero cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(66)) [
<xref rid="B63-viruses-10-00721" ref-type="bibr">63</xref>
].</p>
<p>Interferon alpha1 (IFN-α1) and cyclosporine (CsA) have additive or synergistic effects in limiting MERS-CoV replication in ex vivo cultures of human bronchus (
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(67)) [
<xref rid="B72-viruses-10-00721" ref-type="bibr">72</xref>
]. In addition, the combined treatment of IFN-α1 and CsA has the most potent effect on inducing interferon-stimulated genes (ISGs) in both lung (24 hpi) and bronchial (56 hpi) tissues [
<xref rid="B72-viruses-10-00721" ref-type="bibr">72</xref>
].</p>
<p>Saracatinib, a potent inhibitor of the Src-family of tyrosine kinases (SFK), potently inhibits MERS-CoV with an EC
<sub>50</sub>
of about 3 μM in Huh-7 cells (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(68)) [
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]. It possibly inhibits MERS-CoV replication through the suppression of SFK signaling pathways at the early stages of the viral life cycle [
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]. In addition, another seven compounds, primarily classified as antiprotozoal, anticancer, and antipsychotic, were also determined by complete dose-response analyses (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(69–75)) [
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
].</p>
<p>A spectrum-inhibitor, FA-613, can inhibit MERS-CoV with an EC
<sub>50</sub>
of ~10 μM in the interferon-competent cell line of Huh-7 cells, as shown by MTT assay (
<xref rid="viruses-10-00721-t002" ref-type="table">Table 2</xref>
;
<xref ref-type="fig" rid="viruses-10-00721-f005">Figure 5</xref>
(76)) [
<xref rid="B65-viruses-10-00721" ref-type="bibr">65</xref>
].</p>
</sec>
</sec>
<sec id="sec4-viruses-10-00721">
<title>4. Strategies for Developing Small-Molecule MERS-CoV Inhibitors</title>
<p>The luciferase-based biosensor assay is a cell-based screening assay for selecting MERS-CoV-specific or broad-spectrum coronavirus PL
<sub>pro</sub>
and 3CL
<sub>pro</sub>
inhibitors [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. HEK293T cells were transfected by two artificial plasmids: protease expression plasmids and biosensor expression plasmids [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. Protease expression plasmids contain the sequence of MERS-CoV PL
<sub>pro</sub>
, the nonstructural proteins nsp4 and nsp5, as well as the N-terminal 6 region. Biosensor expression plasmids contain a circularly permuted
<italic>Photuris pennsylvanica</italic>
luciferase and the amino sequence of cleavage site of PL
<sub>pro</sub>
or 3CL
<sub>pro</sub>
[
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. After cell transfection and coexpression of a MERS-CoV protease domain with a cleavage-activated luciferase substrate, transfected live cells allow for both endpoint evaluation and live cell imaging profiles of protease activity [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]. This novel method can be performed in a biosafety level 2 research laboratory to evaluate the ability to inhibit the CoV protease activity of existing and new drugs [
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
].</p>
<p>Pseudovirus-based screening assays have been developed for identifying antiviral compounds in the MERS-CoV life cycle without using infectious viruses. The MERS-CoV pseudovirus allows for single-cycle infection of a variety of cells expressing DPP4, and results are consistent with those from a live MERS-CoV-based inhibition assay. More importantly, the pseudovirus assay can be carried out in a BSL-2, rather than a BSL-3 facility [
<xref rid="B9-viruses-10-00721" ref-type="bibr">9</xref>
]. VSV- and HIV-luciferase pseudotyped with the MERS-CoV S protein are two more approaches [
<xref rid="B27-viruses-10-00721" ref-type="bibr">27</xref>
].</p>
<p>Structure-Guided Design and Optimization of Small Molecules is a strategy that involves embodying a piperidine moiety as a design element to attain optimal pharmacological activity and protein kinase property [
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
]. This strategy permits the resultant hybrid inhibitor to participate in favorable binding interactions with the S3 and S4 subsites of 3CL
<sub>pro</sub>
by attaching the piperidine moiety to a dipeptidyl component [
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
].</p>
<p>Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the PL
<sub>pro</sub>
domain in coronavirus polyproteins. In the past, the role of Ubl2 in PL
<sub>pro</sub>
has remained undefined. However, evidence indicates that removing the Ubl2 domain from MERS PL
<sub>pro</sub>
has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins [
<xref rid="B73-viruses-10-00721" ref-type="bibr">73</xref>
].</p>
<p>Analyzing the transcriptome of hosts infected with MERS-CoV can provide insight into how MERS-CoV infection influences and interacts with host cells. Josset et al. [
<xref rid="B74-viruses-10-00721" ref-type="bibr">74</xref>
] infected a lung epithelial cell line, Calu3, with MERS-CoV and analyzed the transcriptome to identify inhibitory compounds resident in host factors that could be exploited as antiviral therapeutics. This approach can be used to identify host factors beneficial for virus propagation, thus establishing appropriate targets for existing or new antiviral inhibitors.</p>
</sec>
<sec id="sec5-viruses-10-00721">
<title>5. Conclusions</title>
<p>As a positive-sense, single-stranded RNA virus, MERS-CoV utilizes host cellular components to accomplish various physiological processes, including viral entry, genomic replication, and the assembly and budding of virions, thereby resulting in pathological damage to the host. Therefore, various stages of virus life cycle could be potential targets for developing small-molecule antiviral inhibitors. Inhibitors blocking MERS-CoV entry into host cells, viral protease inhibitors, and inhibitors targeting host cells and many other small-molecule inhibitors with defined or undefined mechanisms of action are summarized in this review.</p>
<p>Any compounds that interfere with virus infection may be harmful to host cells. Therefore, the establishment of a safety profile is essential. Furthermore, an antiviral inhibitor should effectively inhibit the growth of the virus because a small amount of virion replication can lead to resistant mutations. The advantages of small-molecule inhibitors include low price, stability, and the convenience of oral administration. Three main approaches are currently used to develop MERS-CoV small-molecule inhibitors. The first is the de novo synthesis of inhibitors targeting the unique structure in the proteins of MERS-CoV appearing in its infection process. The second approach involves screening inhibitors against MERS-CoV infection from an existing drug database by various chemical synthesis strategies. The third approach involves changing the chemical group of a fully developed drug to enhance its pharmacological activity against MERS-CoV. More novel strategies in improving the efficacy of screening small-molecule inhibitors are anticipated to reduce the threat of future MERS-CoV infections.</p>
</sec>
</body>
<back>
<notes>
<title>Author Contributions</title>
<p>R.L., L.W., N.Z., X.D., M.S., Y.S., L.H., and C.H. drafted the manuscript. T.Y., S.J., and F.Y. revised and edited the manuscript.</p>
</notes>
<notes>
<title>Funding</title>
<p>This work was supported by grants from the National Natural Science Foundation of China (81501735 and 81601761), Hebei Province’s Program for Talents Returning from Studying Overseas (CN201707), a starting grant from Hebei Agricultural University (ZD2016026), and the Program for Youth Talent of Higher Learning Institutions of Hebei Province (BJ2018045).</p>
</notes>
<notes notes-type="COI-statement">
<title>Conflicts of Interest</title>
<p>The authors declare no conflict of interest.</p>
</notes>
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<name>
<surname>O’Brien</surname>
<given-names>A.</given-names>
</name>
<name>
<surname>Baker</surname>
<given-names>S.C.</given-names>
</name>
<name>
<surname>Mesecar</surname>
<given-names>A.D.</given-names>
</name>
</person-group>
<article-title>X-ray structure and enzymatic activity profile of a core papain-like protease of mers coronavirus with utility for structure-based drug design</article-title>
<source>Sci. Rep.</source>
<year>2017</year>
<volume>7</volume>
<fpage>40292</fpage>
<pub-id pub-id-type="doi">10.1038/srep40292</pub-id>
<pub-id pub-id-type="pmid">28079137</pub-id>
</element-citation>
</ref>
<ref id="B74-viruses-10-00721">
<label>74.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Josset</surname>
<given-names>L.</given-names>
</name>
<name>
<surname>Menachery</surname>
<given-names>V.D.</given-names>
</name>
<name>
<surname>Gralinski</surname>
<given-names>L.E.</given-names>
</name>
<name>
<surname>Agnihothram</surname>
<given-names>S.</given-names>
</name>
<name>
<surname>Sova</surname>
<given-names>P.</given-names>
</name>
<name>
<surname>Carter</surname>
<given-names>V.S.</given-names>
</name>
<name>
<surname>Yount</surname>
<given-names>B.L.</given-names>
</name>
<name>
<surname>Graham</surname>
<given-names>R.L.</given-names>
</name>
<name>
<surname>Baric</surname>
<given-names>R.S.</given-names>
</name>
<name>
<surname>Katze</surname>
<given-names>M.G.</given-names>
</name>
</person-group>
<article-title>Cell host response to infection with novel human coronavirus emc predicts potential antivirals and important differences with sars coronavirus</article-title>
<source>mBio</source>
<year>2013</year>
<volume>4</volume>
<fpage>e00165-13</fpage>
<pub-id pub-id-type="doi">10.1128/mBio.00165-13</pub-id>
<pub-id pub-id-type="pmid">23631916</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
<floats-group>
<fig id="viruses-10-00721-f001" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>Summary of morbidity statistics with country- and quarter-level panel data.</p>
</caption>
<graphic xlink:href="viruses-10-00721-g001"></graphic>
</fig>
<fig id="viruses-10-00721-f002" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>Schematic diagram of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. MERS-CoV enters host cells by plasma membrane fusion (membrane fusion) or endosomal membrane fusion (endocytosis), and then releases the viral RNA into the cytoplasm. The RNA genome is replicated and viral proteins are produced. The progeny virus is generated and released from the infected cells.</p>
</caption>
<graphic xlink:href="viruses-10-00721-g002"></graphic>
</fig>
<fig id="viruses-10-00721-f003" orientation="portrait" position="float">
<label>Figure 3</label>
<caption>
<p>Schematic representation of MERS-CoV S (spike) protein S1 subunit and S2 subunit. RBD, receptor binding domain; FP, fusion peptide; HR1, heptad repeat 1 domain; HR2, heptad repeat 2 domain; TM, transmembrane domain; CP, cytoplasmic domain. The residue numbers of each region correspond to their positions in the S protein of MERS-CoV. HR2P, the peptide derived from the HR2 domain of MERS-CoV S protein S2 subunit; HR2P-M2, HR2P analogous peptide with mutations.</p>
</caption>
<graphic xlink:href="viruses-10-00721-g003"></graphic>
</fig>
<fig id="viruses-10-00721-f004" orientation="portrait" position="float">
<label>Figure 4</label>
<caption>
<p>Schematic representation of the inhibition mechanism of HR2P and HR2P-M2. ① Target cell membrane; ② MERS-CoV; ③ dipeptidyl peptidase-4 (DPP4). (
<bold>A</bold>
) Mechanism of normal binding between a host cell and MERS-CoV. MERS-CoV enters the host cell by binding the viral particle via the RBD in spike protein to the cellular receptorDPP4 on the surface of the host cell. The HR2 binds to the HR1 to form a six-helix bundle (6-HB) fusion core, which brings viral and cell membranes into close apposition for fusion. (
<bold>B</bold>
) HR2P and HR2P-M2 block six-bundle fusion core formation between HR1 and HR2 peptides by binding to the viral S protein HR1 domain.</p>
</caption>
<graphic xlink:href="viruses-10-00721-g004"></graphic>
</fig>
<fig id="viruses-10-00721-f005" orientation="portrait" position="float">
<label>Figure 5</label>
<caption>
<p>Chemical structure formulae of small-molecule inhibitors of MERS-CoV described in this review.</p>
</caption>
<graphic xlink:href="viruses-10-00721-g005a"></graphic>
<graphic xlink:href="viruses-10-00721-g005b"></graphic>
<graphic xlink:href="viruses-10-00721-g005c"></graphic>
<graphic xlink:href="viruses-10-00721-g005d"></graphic>
<graphic xlink:href="viruses-10-00721-g005e"></graphic>
<graphic xlink:href="viruses-10-00721-g005f"></graphic>
<graphic xlink:href="viruses-10-00721-g005g"></graphic>
<graphic xlink:href="viruses-10-00721-g005h"></graphic>
</fig>
<table-wrap id="viruses-10-00721-t001" orientation="portrait" position="float">
<object-id pub-id-type="pii">viruses-10-00721-t001_Table 1</object-id>
<label>Table 1</label>
<caption>
<p>Peptide viral inhibitors against MERS-CoV.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Compound</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Sequence</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Testing Model</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Lines Tested</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">EC
<sub>50</sub>
(μM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CC
<sub>50</sub>
(μM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="7" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">
<bold>Peptide inhibitors disturbing membrane fusion</bold>
</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">HR2P</td>
<td align="center" valign="middle" rowspan="1" colspan="1">SLTQINTTLLDLTYEMLSLQQVVKALNESYIDLKEL</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero cells
<break></break>
Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.6
<break></break>
0.93 ± 0.15
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>1000</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">HR2P-M2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">SLTQINTTLLDLEYEMKKLEEVVKKLEESYIDLKEL</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro; in vivo:
<break></break>
hDPP4 Tg mice</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Calu-3 and Vero cells; Ad5-hDPP4 mice</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.55 ± 0.04
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B16-viruses-10-00721" ref-type="bibr">16</xref>
,
<xref rid="B18-viruses-10-00721" ref-type="bibr">18</xref>
,
<xref rid="B19-viruses-10-00721" ref-type="bibr">19</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQQVV K*LNE*Y</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.97 ± 0.08; 0.33 ± 0.04
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">L*LTY*M LSLQQVV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.90 ± 1.1
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLT*EM L*LQQVV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.14 ± 0.7
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM *SLQ*VV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.7 ± 2.6
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQ*VV K*LNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.03 ± 0.29;
<break></break>
0.26 ± 0.05
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQQVV *ALN*SY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">14.1 ± 2.3
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LXLTYXM LSLQQVV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.9 ± 1.1
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTXEM LXLQQVV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.21 ± 0.9
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM XSLQXVV KALNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.49 ± 0.6
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQXVV KXLNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">20.6 ± 3.3
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQQVV XALNXSY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.9 ± 1.0
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21L10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQQVV KXLNEXY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.55 ± 0.2
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21R8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQ^VV K^LNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">16.3 ± 1.1
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S8Z</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEZ LSLQ*VV K*LNESY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.80 ± 0.74;
<break></break>
0.63 ± 0.05
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S8F</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYEM LSLQ*VV K*LNESF</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.16 ± 1.1
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P21S8ZF</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LDLTYES LSLQ*VV K*LNESF</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.89 ± 0.8
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B20-viruses-10-00721" ref-type="bibr">20</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">P9
<sup>a</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">NGAICWGPCPTAFRQIGNCGHFKVRCCKIR</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">MDCK cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.00 μg/mL</td>
<td align="center" valign="middle" rowspan="1" colspan="1">380 μg/mL</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B21-viruses-10-00721" ref-type="bibr">21</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">LLS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LEELSKKLEELSKKLEELSKKLEELSKKLEELSKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.24 ± 0.08
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.04 ± 0.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEISKKIEEISKKIEEISKKIEEISKKIEEISKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.10 ± 0.02
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">88.8 ± 28</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">AAS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">AEEASKKAEEASKKAEEASKKAEEASKKAEEASKK-βA-K(C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.47 ± 1.7
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.38 ± 0.9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">FFS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">FEEFSKKFEEFSKKFEEFSKKFEEFSKKFEEFSKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.11 ± 0.9
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">YYS</td>
<td align="center" valign="middle" rowspan="1" colspan="1">YEEYSKKYEEYSKKYEEYSKKYEEYSKKYEEYSKK-βA-K(C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro </td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.26 ± 2.1
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">19.8 ± 1.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIY</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEIYKKIEEIYKKIEEIYKKIEEIYKKIEEIYKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro </td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.52 ± 0.4
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIW</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEIWKKIEEIWKKIEEIWKKIEEIWKKIEEIWKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.6 ± 2.4
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIH</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEIHKKIEEIHKKIEEIHKKIEEIHKKIEEIHKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.68 ± 0.47
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIQ</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEIQKKIEEIQKKIEEIQKKIEEIQKKIEEIQKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.13 ± 0.1;
<break></break>
0.11 ± 0.02
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">IIK</td>
<td align="center" valign="middle" rowspan="1" colspan="1">IEEIKKKIEEIKKKIEEIKKKIEEIKKKIEEIKKK-βA-K (C16)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.45 ± 0.13
<sup>b</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.54 ± 0.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IIE</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IEEIEKKIEEIEKKIEEIEKKIEEIEKKIEEIEKK-βA-K (C16)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.93 ± 0.95
<sup>b</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B22-viruses-10-00721" ref-type="bibr">22</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>
<sup>a</sup>
P9-aci-1: three acidic amino acids D, E, and D were added to the C-terminus of P9.
<sup>b</sup>
Concentration of peptide that blocks MERS-CoV S-mediated cell–cell fusion. “-” indicates data not available. “*” indicates the position of the S5 residues, which react to form the all hydrocarbon staple. “^” indicates the positions of the R5 amino acids, which react to form staples. EC
<sub>50</sub>
: concentration for 50% of maximal effect. CC
<sub>50</sub>
: the 50% cytotoxicity concentrations.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="viruses-10-00721-t002" orientation="portrait" position="float">
<object-id pub-id-type="pii">viruses-10-00721-t002_Table 2</object-id>
<label>Table 2</label>
<caption>
<p>Small molecule viral inhibitors against MERS-CoV.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Inhibitor</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Testing Model</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Lines</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">EC
<sub>50</sub>
(μM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CC
<sub>50</sub>
(μM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">
<bold>Inhibitors blocking the binding between virus and host cells</bold>
</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ADS-J1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NBL-7 and Huh-7 cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">26.9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B27-viruses-10-00721" ref-type="bibr">27</xref>
]</td>
</tr>
<tr>
<td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">
<bold>Inhibitors disrupting endocytosis</bold>
</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Chlorpromazine </td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">23.33 ± 2.89
<sup>a</sup>
;
<break></break>
49 ± 1.2;
<break></break>
9.514</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>40;
<break></break>
21.3 ± 1.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B5-viruses-10-00721" ref-type="bibr">5</xref>
,
<xref rid="B6-viruses-10-00721" ref-type="bibr">6</xref>
,
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
,
<xref rid="B26-viruses-10-00721" ref-type="bibr">26</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Promethazine </td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">16.67 ± 7.22
<sup>a</sup>
;
<break></break>
11.802</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>40</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
,
<xref rid="B26-viruses-10-00721" ref-type="bibr">26</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Fluphenazine </td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">15.00 ± 4.33
<sup>a</sup>
;
<break></break>
5.868</td>
<td align="center" valign="middle" rowspan="1" colspan="1">~40</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
,
<xref rid="B26-viruses-10-00721" ref-type="bibr">26</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">K11777</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.046</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B32-viruses-10-00721" ref-type="bibr">32</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Camostat</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero-TMPRSS2 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">~1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B31-viruses-10-00721" ref-type="bibr">31</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Ouabain</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">~0.05</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B35-viruses-10-00721" ref-type="bibr">35</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Bufalin</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.01–0.015</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B35-viruses-10-00721" ref-type="bibr">35</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dihydrotanshinone</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.5–1 μg/mL</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B36-viruses-10-00721" ref-type="bibr">36</xref>
]</td>
</tr>
<tr>
<td colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">
<bold>Inhibitors interrupting MERS-CoV MERS-CoV RNA replication and translation</bold>
</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Disulfiram</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">22.7 ± 0.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B47-viruses-10-00721" ref-type="bibr">47</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>3k</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.8 ± 1.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>3h</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.3 ± 2.1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>3i</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.4 ± 2.2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B48-viruses-10-00721" ref-type="bibr">48</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">CE-5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">HEK293T cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">~12.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B53-viruses-10-00721" ref-type="bibr">53</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>6b</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.4 ± 0.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B54-viruses-10-00721" ref-type="bibr">54</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>6c</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.2 ± 0.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B54-viruses-10-00721" ref-type="bibr">54</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>6d</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.6 ± 0.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">58.6 ± 1.2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B54-viruses-10-00721" ref-type="bibr">54</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">GC376</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.56 ± 0.09;
<break></break>
0.9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>150</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
,
<xref rid="B55-viruses-10-00721" ref-type="bibr">55</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">GC813</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>10a</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero81 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>10c</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero81 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B52-viruses-10-00721" ref-type="bibr">52</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.28 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B56-viruses-10-00721" ref-type="bibr">56</xref>
]</td>
</tr>
<tr>
<td colspan="6" align="center" valign="middle" rowspan="1">
<bold>Inhibitors with undefined mechanisms</bold>
</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">Silvestrol</td>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">MRC-5 cells</td>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">0.0013</td>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">0.4</td>
<td align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1">[
<xref rid="B57-viruses-10-00721" ref-type="bibr">57</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">GS-5734</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">HAE cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.074 ± 0.023</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">GS-441524</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">HAE cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.86 ± 0.78</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B58-viruses-10-00721" ref-type="bibr">58</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Chloroquine</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">MDMs and MDDCs cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.0 ± 1.1;
<break></break>
6.275</td>
<td align="center" valign="middle" rowspan="1" colspan="1">58.1 ± 1.1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
,
<xref rid="B59-viruses-10-00721" ref-type="bibr">59</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Emetine dihydrochloride hydrate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.014</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Hydroxychloroquine sulfate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.279</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Mefloquine</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.416</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Amodiaquine dihydrochloride dehydrate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.212</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">E-64-D</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.275</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Gemcitabine hydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.216</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Tamoxifen citrate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.117</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Toremifene citrate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12.915</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Terconazole</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12.203</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Triparanol</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.283</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Anisomycin</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.003</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Cycloheximide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.189</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Homoharringtonine</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.0718</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Benztropine mesylate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">16.627</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Fluspirilene</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.477</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Thiothixene</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.297</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Astemizole</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.884</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Chlorphenoxamine hydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12.646</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Thiethylperazine maleate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7.865</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Triflupromazine hydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.758</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Clomipramine hydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.332</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Imatinib mesylate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">17.689</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Dasatinib</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.468</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Loperamide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.8 ± 1.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">15.5 ± 1.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Lopinavir</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">8.0 ± 1.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">24.4 ± 1.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B7-viruses-10-00721" ref-type="bibr">7</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">SSYA10-001</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">~25</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>500</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B60-viruses-10-00721" ref-type="bibr">60</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">ESI-09</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Calu-3 and Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5–10</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>50</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B61-viruses-10-00721" ref-type="bibr">61</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Mycophenolic acid</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro </td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero E6 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.87</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B60-viruses-10-00721" ref-type="bibr">60</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">BCX4430</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" rowspan="1" colspan="1">68.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B62-viruses-10-00721" ref-type="bibr">62</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Fleximer analogues 2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Vero cells
<break></break>
Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">23 ± 0.6;
<break></break>
27 ± 0.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">71 ± 14;
<break></break>
149 ± 6.8</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B63-viruses-10-00721" ref-type="bibr">63</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Nutlin-3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.9 ± 1.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">26.8 ± 1.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Amodiaquine dihydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.1 ± 0.7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12.3 ± 5.9</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Saracatinib</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.9 ± 0.6</td>
<td align="center" valign="middle" rowspan="1" colspan="1">57 ± 5.5</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Sotrastaurin</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.7 ± 3.3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>50</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Acetophenazine maleate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">11.2 ± 5.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">23.6 ± 3.8</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Dosulepin hydrochloride</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.4 ± 0.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">28.9 ± 0.0</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Methotrimeprazine maleate salt</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.5 ± 0.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">24.5 ± 0.0</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">N1-(4-pyridyl)-2-chloro-5-nitrobenzamide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.5 ± 0.3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">>50</td>
<td align="center" valign="top" rowspan="1" colspan="1">[
<xref rid="B64-viruses-10-00721" ref-type="bibr">64</xref>
]</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">FA-613</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huh-7 cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10.2 ± 0.2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[
<xref rid="B65-viruses-10-00721" ref-type="bibr">65</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>
<sup>a</sup>
50% effective concentration (EC
<sub>50</sub>
) values of inhibiting cell−cell fusion. “-” indicates data not available.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>

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