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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro</title><author><name sortKey="Choy, Ka Tim" sort="Choy, Ka Tim" uniqKey="Choy K" first="Ka-Tim" last="Choy">Ka-Tim Choy</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Wong, Alvina Yin Lam" sort="Wong, Alvina Yin Lam" uniqKey="Wong A" first="Alvina Yin-Lam" last="Wong">Alvina Yin-Lam Wong</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Kaewpreedee, Prathanporn" sort="Kaewpreedee, Prathanporn" uniqKey="Kaewpreedee P" first="Prathanporn" last="Kaewpreedee">Prathanporn Kaewpreedee</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Sia, Sin Fun" sort="Sia, Sin Fun" uniqKey="Sia S" first="Sin Fun" last="Sia">Sin Fun Sia</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chen, Dongdong" sort="Chen, Dongdong" uniqKey="Chen D" first="Dongdong" last="Chen">Dongdong Chen</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Hui, Kenrie Pui Yan" sort="Hui, Kenrie Pui Yan" uniqKey="Hui K" first="Kenrie Pui Yan" last="Hui">Kenrie Pui Yan Hui</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chu, Daniel Ka Wing" sort="Chu, Daniel Ka Wing" uniqKey="Chu D" first="Daniel Ka Wing" last="Chu">Daniel Ka Wing Chu</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chan, Michael Chi Wai" sort="Chan, Michael Chi Wai" uniqKey="Chan M" first="Michael Chi Wai" last="Chan">Michael Chi Wai Chan</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Cheung, Peter Pak Hang" sort="Cheung, Peter Pak Hang" uniqKey="Cheung P" first="Peter Pak-Hang" last="Cheung">Peter Pak-Hang Cheung</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Huang, Xuhui" sort="Huang, Xuhui" uniqKey="Huang X" first="Xuhui" last="Huang">Xuhui Huang</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Yen, Hui Ling" sort="Yen, Hui Ling" uniqKey="Yen H" first="Hui-Ling" last="Yen">Hui-Ling Yen</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32251767</idno><idno type="pmc">7127386</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127386</idno><idno type="RBID">PMC:7127386</idno><idno type="doi">10.1016/j.antiviral.2020.104786</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000826</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000826</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro</title><author><name sortKey="Choy, Ka Tim" sort="Choy, Ka Tim" uniqKey="Choy K" first="Ka-Tim" last="Choy">Ka-Tim Choy</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Wong, Alvina Yin Lam" sort="Wong, Alvina Yin Lam" uniqKey="Wong A" first="Alvina Yin-Lam" last="Wong">Alvina Yin-Lam Wong</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Kaewpreedee, Prathanporn" sort="Kaewpreedee, Prathanporn" uniqKey="Kaewpreedee P" first="Prathanporn" last="Kaewpreedee">Prathanporn Kaewpreedee</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Sia, Sin Fun" sort="Sia, Sin Fun" uniqKey="Sia S" first="Sin Fun" last="Sia">Sin Fun Sia</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chen, Dongdong" sort="Chen, Dongdong" uniqKey="Chen D" first="Dongdong" last="Chen">Dongdong Chen</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Hui, Kenrie Pui Yan" sort="Hui, Kenrie Pui Yan" uniqKey="Hui K" first="Kenrie Pui Yan" last="Hui">Kenrie Pui Yan Hui</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chu, Daniel Ka Wing" sort="Chu, Daniel Ka Wing" uniqKey="Chu D" first="Daniel Ka Wing" last="Chu">Daniel Ka Wing Chu</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Chan, Michael Chi Wai" sort="Chan, Michael Chi Wai" uniqKey="Chan M" first="Michael Chi Wai" last="Chan">Michael Chi Wai Chan</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Cheung, Peter Pak Hang" sort="Cheung, Peter Pak Hang" uniqKey="Cheung P" first="Peter Pak-Hang" last="Cheung">Peter Pak-Hang Cheung</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Huang, Xuhui" sort="Huang, Xuhui" uniqKey="Huang X" first="Xuhui" last="Huang">Xuhui Huang</name><affiliation><nlm:aff id="aff2">Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Peiris, Malik" sort="Peiris, Malik" uniqKey="Peiris M" first="Malik" last="Peiris">Malik Peiris</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author><author><name sortKey="Yen, Hui Ling" sort="Yen, Hui Ling" uniqKey="Yen H" first="Hui-Ling" last="Yen">Hui-Ling Yen</name><affiliation><nlm:aff id="aff1">School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</nlm:aff></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Agostini, M L" uniqKey="Agostini M">M.L. Agostini</name></author><author><name sortKey="Andres, E L" uniqKey="Andres E">E.L. Andres</name></author><author><name sortKey="Sims, A C" uniqKey="Sims A">A.C. Sims</name></author><author><name sortKey="Graham, R L" uniqKey="Graham R">R.L. Graham</name></author><author><name sortKey="Sheahan, T P" uniqKey="Sheahan T">T.P. Sheahan</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X. Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andersen, P I" uniqKey="Andersen P">P.I. Andersen</name></author><author><name sortKey="Krpina, K" uniqKey="Krpina K">K. Krpina</name></author><author><name sortKey="Ianevski, A" uniqKey="Ianevski A">A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res</journal-id><journal-title-group><journal-title>Antiviral Research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn><publisher><publisher-name>Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32251767</article-id><article-id pub-id-type="pmc">7127386</article-id><article-id pub-id-type="publisher-id">S0166-3542(20)30200-X</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2020.104786</article-id><article-id pub-id-type="publisher-id">104786</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Choy</surname><given-names>Ka-Tim</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Wong</surname><given-names>Alvina Yin-Lam</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Kaewpreedee</surname><given-names>Prathanporn</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Sia</surname><given-names>Sin Fun</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Chen</surname><given-names>Dongdong</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au6"><name><surname>Hui</surname><given-names>Kenrie Pui Yan</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au7"><name><surname>Chu</surname><given-names>Daniel Ka Wing</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au8"><name><surname>Chan</surname><given-names>Michael Chi Wai</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au9"><name><surname>Cheung</surname><given-names>Peter Pak-Hang</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au10"><name><surname>Huang</surname><given-names>Xuhui</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au11"><name><surname>Peiris</surname><given-names>Malik</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au12"><name><surname>Yen</surname><given-names>Hui-Ling</given-names></name><email>hyen@hku.hk</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China</aff><aff id="aff2"><label>b</label>Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong SAR, China</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. <email>hyen@hku.hk</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>3</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>6</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>3</day><month>4</month><year>2020</year></pub-date><volume>178</volume><fpage>104786</fpage><lpage>104786</lpage><history><date date-type="received"><day>15</day><month>3</month><year>2020</year></date><date date-type="rev-recd"><day>28</day><month>3</month><year>2020</year></date><date date-type="accepted"><day>29</day><month>3</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 Elsevier B.V. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Elsevier B.V.</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0010"><p>An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.</p></abstract><abstract abstract-type="author-highlights" id="abs0015"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">Remdesivir inhibits SARS-CoV-2 replication in Vero-E6 cells with EC<sub>50</sub> at 23.15 μM.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">Lopinavir but not ritonavir inhibits SARS-CoV-2 replication with EC<sub>50</sub> at 26.63 μM.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">Homoharringtonine and emetine inhibits SARS-CoV-2 replication with EC<sub>50</sub> at 2.55 and 0.46 μM, respectively.</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">Combination of remdesivir and emetine showed synergistic effect in vitro.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>COVID-19</kwd><kwd>Remdesivir</kwd><kwd>Lopinavir</kwd><kwd>Ritonavir</kwd><kwd>Emetine</kwd><kwd>Homoharringtonine</kwd><kwd>ABSTRACT</kwd></kwd-group></article-meta></front><body><p id="p0030">Within three months of the first identification of SARS-CoV-2 virus in Wuhan, Hubei Province, China, the world is facing an escalating pandemic that will have significant impacts on global health systems and economy (<xref rid="bib32" ref-type="bibr">WHO, 2019</xref>). Infection with the novel SARS-CoV-2 virus may lead to a wide range of clinical presentations from asymptomatic infection in 1% of laboratory confirmed cases to mild, severe, and critical infections in 81%, 14%, and 5% of symptomatic cases, respectively (<xref rid="bib34" ref-type="bibr">Wu and McGoogan, 2020</xref>). The estimated symptomatic case-fatality risk (sCFR) among cases in Wuhan was 1.4%, and those aged above 59 were 5.1 times more likely to die from infection than those aged 30–59 years (<xref rid="bib35" ref-type="bibr">Wu et al., 2020</xref>). With an estimated basic reproductive number of 2.2 (95% CI, 1.4–3.9) (<xref rid="bib20" ref-type="bibr">Li et al., 2020</xref>), the virus will continue to spread and infect 55% of the global population over time if no effective vaccine is developed (<xref rid="bib15" ref-type="bibr">Fine et al., 2011</xref>). There is currently no effective antiviral compound licensed for the treatment against human coronaviruses or SARS-CoV-2.</p><p id="p0035">The SARS-CoV-2 virus shared 79.5% genetic homology to the SARS-CoV and both are descendants of bat coronaviruses within the <italic>Betacoronavirus</italic> genus (<xref rid="bib37" ref-type="bibr">Zhou et al., 2020</xref>). Antiviral compounds previously reported to show effect against SARS-CoV or other coronaviruses may be effective against SARS-CoV-2 (<xref rid="bib9" ref-type="bibr">Chu et al., 2004</xref>; <xref rid="bib11" ref-type="bibr">de Wilde et al., 2014</xref>; <xref rid="bib14" ref-type="bibr">Dyall et al., 2014</xref>; <xref rid="bib30" ref-type="bibr">Shen et al., 2019</xref>; <xref rid="bib4" ref-type="bibr">Cao et al., 2015</xref>). In addition, remdesivir (GS-5734), a prodrug of adenosine analog with a broad-spectrum antiviral activity against filoviruses, paramyxoviruses, and coronaviruses (<xref rid="bib3" ref-type="bibr">Brown et al., 2019</xref>; <xref rid="bib29" ref-type="bibr">Sheahan et al., 2017</xref>; <xref rid="bib12" ref-type="bibr">de Wit et al., 2020</xref>), was recently confirmed to inhibit 2019-nCoV in vitro (<xref rid="bib31" ref-type="bibr">Wang et al., 2020</xref>). According to the 7th edition of the novel coronavirus diagnosis and treatment plan issued by the National Health Commission of the People's Republic of China, options for antiviral therapy include aerosolized α-interferon, lopinavir/ritonavir, ribavirin in combination with lopinavir/ritonavir, chloroquine phosphate, or Arbidol (<xref rid="bib7" ref-type="bibr">China National Health Commission, 2020</xref>). Ongoing clinical trials are evaluating the efficacy of remdesivir, and various HIV-protease inhibitors (lopinavir/ritonavir, ASC09/ritonavir, darunavir), reverse transcriptase inhibitor (Azvudine), anti-influenza compounds, interferon alfa-2b, or monoclonal antibody targeting PD-1 (Camrelizumab) or IL-6 (Tocilizumab) (<xref rid="bib8" ref-type="bibr">Chinese Clinical Trial Re</xref>). We evaluated the anti-SARS-CoV-2 effect of compounds that have been under development or already approved for other clinical applications; some compounds were previously reported to inhibit coronavirus replication in vitro, and some are evaluated in clinical trials in patients with coronavirus disease (COVID-19).</p><p id="p0040">SARS-CoV-2 virus, BetaCoV/Hong Kong/VM20001061/2020, was isolated from the nasopharynx aspirate and throat swab of a confirmed COVID-19 patient in Hong Kong using Vero E6 cells (ATCC CRL-1586). Stock virus (10<sup>7.25</sup> TCID<sub>50</sub>/mL) was prepared after three serial passages in Vero E6 cells in infection media (DMEM supplemented with 4.5 g/L D-glucose, 100 mg/L sodium pyruvate, 2% FBS, 100,000 U/L Penicillin-Streptomycin, and 25 mM HEPES). Compounds were sourced from MedChemExpress and Sigma-Aldrich and the stocks were prepared with DMSO (50 mM remdesivir, 100 mM favipiravir, 10 mM R-1479, 10 mM tenofovir, 10 mM fludarabine phosphate, 10 mM baloxavir, 10 mM chlorpromazine hydrochloride, 5 mM dalbavancin hydrochloride, 10 mM homoharringtonine, 10 mM lopinavir, 10 mM ritonavir) or with water (5 mM emetine dihydrochloride, 10 mM galidesivir hydrochloride, 50 mM ribavirin, 2.5 mM oritavancin diphosphate). Oseltamivir carboxylate (10 mM in water) was provided by Roche. To evaluate the effect of compounds in vitro, Vero E6 cells were pre-treated with compounds diluted in infection media for 1 h prior to infection by SARS-CoV-2 virus at MOI = 0.02. Antiviral compounds were maintained with the virus inoculum during the 2-h incubation period. The inoculum was removed after incubation, and the cells were overlaid with infection media containing diluted compounds. After 48 h incubation at 37 °C, supernatants were collected to quantify viral loads by TCID<sub>50</sub> assay or quantitative real-time RT-PCR (TaqMan™ Fast Virus 1-Step Master Mix) following the methods described (<xref rid="bib10" ref-type="bibr">Chu et al., 2020</xref>). Four-parameter logistic regression (GraphPad Prism) was used to fit the dose-response curves and determined the 50% effective concentrations (EC<sub>50</sub>) of the compounds that inhibit viral replication. Cytotoxicty of selected compounds was evaluated in Vero E6 cells using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega).</p><p id="p0045">Among the 16 compounds we tested, remdesivir, lopinavir, homoharringtonine, and emetine dihydrochloride were found to inhibit SARS-CoV-2 replication in Vero E6 cells with EC<sub>50</sub> under 100 μM (<xref rid="tbl1" ref-type="table">Table 1</xref>). Importantly, we observed that some of the compounds currently undergoing clinical trials such as ribavirin, favipiravir, oseltamivir, or baloxavir showed no apparent antiviral effect against the SARS-CoV-2 virus in vitro at concentrations under 100 μM (<xref rid="tbl1" ref-type="table">Table 1</xref>). Remdesivir is a 1′-cyano-substituted adenosine analogue that has been shown to inhibit human coronaviruses (hCoV-OC43 and hCoV-229E) SARS-CoV, MERS-CoV, and SARS-CoV-2 (<xref rid="bib3" ref-type="bibr">Brown et al., 2019</xref>; <xref rid="bib29" ref-type="bibr">Sheahan et al., 2017</xref>; <xref rid="bib12" ref-type="bibr">de Wit et al., 2020</xref>). It is currently evaluated in phase 4 clinical trials for SARS-CoV-2. A recent study fitted viral load in linear scale (eg. the percentage of inhibition) under increasing concentrations of remdesivir reported EC<sub>50</sub> against SARS-CoV-2 virus at 0.77 μM (<xref rid="bib31" ref-type="bibr">Wang et al., 2020</xref>). We fitted viral load in logarithm scale (log<sub>10</sub>TCID<sub>50</sub>/mL and log<sub>10</sub> viral RNA copies/mL) under increasing concentration of remdesivir and determined EC<sub>50</sub> at 23.15 μM and 26.90 μM, respectively (<xref rid="fig1" ref-type="fig">Fig. 1</xref>A and <xref rid="tbl1" ref-type="table">Table 1</xref>). Two mutations (F476L and V553L) in the RNA-dependent RNA polymerase nsp12 of a murine hepatitis virus have been previously reported to confer resistance to remdesivir (<xref rid="bib1" ref-type="bibr">Agostini et al., 2018</xref>). Due to insertions and deletions in nsp12, these two conserved residues are mapped at F480 and V557 in the SARS-CoV-2 isolate (GISAID# EPI_ISL_412028) used for the experiments, which should remain sensitive for remdesivir. Other adenosine analogues (galidesivir, tenofovor, or fludarabine phosphate) or nucleoside analogues (favipiravir, ribavirin, R-1479) did not inhibit viral replication under 100 μM (<xref rid="tbl1" ref-type="table">Table 1</xref>). However, nucleoside analogues require metabolic activation into their triphosphate forms by host cellular nucleoside kinases, which may differ among cell types. Further evaluation of the effect of nucleoside analogues in primary human airway epithelial cells would facilitate the interpretation of the results.<table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Antiviral activity of 16 compounds against SARS-CoV-2 in Vero E6 cells.</p></caption><alt-text id="alttext0020">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th colspan="5">Compounds<hr></hr></th><th colspan="3">Inhibition of SARS-CoV-2 in vitro, μM<hr></hr></th></tr><tr><th>Name</th><th>Bioactivity</th><th>Clinical application</th><th>CAS No.</th><th>CC<sub>50</sub>, μM<xref rid="tbl1fna" ref-type="table-fn">a</xref></th><th>CPE inhibition<xref rid="tbl1fnb" ref-type="table-fn">b</xref></th><th>Reduction in infectious virus<xref rid="tbl1fnc" ref-type="table-fn">c</xref> (EC<sub>50</sub>)</th><th>Reduction in viral RNA copy<xref rid="tbl1fnd" ref-type="table-fn">d</xref> (EC<sub>50</sub>)</th></tr></thead><tbody><tr><td align="left">Remdesivir</td><td align="left">adenosine analogue</td><td align="left">Phase 4 trials for treatment of Ebola or SARS-CoV-2</td><td align="left">1809249-37-3</td><td align="left">>100</td><td align="left">25</td><td align="left">23.15</td><td align="left">26.90</td></tr><tr><td align="left">Favipiravir</td><td align="left">guanine<break></break>analogue</td><td align="left">Approved in Japan and China for treatment of influenza infection</td><td align="left">259793-96-9</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left">Ribavirin</td><td align="left">guanosine analogue</td><td align="left">FDA approved for treatment of chronic hepatitis C infection</td><td align="left">36791-04-5</td><td align="left">>100</td><td align="left">500</td><td align="left">>500</td><td align="left">>500</td></tr><tr><td align="left">Galidesivir</td><td align="left">adenosine analogue</td><td align="left">Phase 2 trial for yellow fever virus infection</td><td align="left">222631-44-9</td><td align="left">>100</td><td align="left">100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left">R-1479</td><td align="left">cytidine<break></break>analogue</td><td align="left">Phase 2 trial for treatment of dengue virus infection</td><td align="left">478182-28-4</td><td align="left">>100</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr><tr><td align="left">Tenofovor</td><td align="left">adenosine analogue</td><td align="left">FDA approved for treatment of HIV-1 and HBV</td><td align="left">147127-20-6</td><td align="left">>100</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr><tr><td align="left">Fludarabine phosphate</td><td align="left">adenosine analogue</td><td align="left">FDA approved for treatment of B-cell chronic lymphocytic leukemia</td><td align="left">75607-67-9</td><td align="left">>100</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr><tr><td align="left">Lopinavir</td><td align="left">protease inhibitor</td><td align="left">FDA approved for treatment of HIV-1 infection in combination with ritonavir</td><td align="left">192725-17-0</td><td align="left">49.75</td><td align="left">25</td><td align="left">26.63</td><td align="left">26.10</td></tr><tr><td align="left">Ritonavir</td><td align="left">protease inhibitor</td><td align="left">FDA approved for treatment of HIV-1 infection in combination with other antiretroviral agents</td><td align="left">155213-67-5</td><td align="left">48.91</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left">Emetine hydrochloride</td><td align="left">anti-protozoal</td><td align="left">Approved in China for severe invasive amoebiasis</td><td align="left">316-42-7</td><td align="left">56.46</td><td align="left">1.5625</td><td align="left">0.46</td><td align="left">0.50</td></tr><tr><td align="left">Oritavancin diphosphate</td><td align="left">antibiotics</td><td align="left">FDA approved treatment for skin infection caused by Gram positive bacteria</td><td align="left">192564-14-0</td><td align="left">N.D.</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr><tr><td align="left">Dalbavancin hydrochloride</td><td align="left">antibiotics</td><td align="left">FDA approved treatment for skin infection caused by Gram positive bacteria</td><td align="left">2227366-51-8</td><td align="left">N.D.</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr><tr><td align="left">Homoharringtonine</td><td align="left">anti-cancer</td><td align="left">FDA approved treatment for chronic myeloid leukemia</td><td align="left">26833-87-4</td><td align="left">59.75</td><td align="left">3.125</td><td align="left">2.55</td><td align="left">2.14</td></tr><tr><td align="left">Oseltamivir carboxylate</td><td align="left">antiviral, neuraminidase inhibitor</td><td align="left">FDA approved treatment for influenza infection</td><td align="left">187227-45-8</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left">Baloxivir acid</td><td align="left">antiviral, endonuclease inhibitor</td><td align="left">FDA approved treatment for influenza infection</td><td align="left">1985605-59-1</td><td align="left">85.90</td><td align="left">>100</td><td align="left">>100</td><td align="left">>100</td></tr><tr><td align="left">Chlorpromazine hydrochloride</td><td align="left">antagonist for post-synaptic receptors</td><td align="left">FDA approved treatment for schizophrenia</td><td align="left">69-09-0</td><td align="left">21.29</td><td align="left">>100</td><td align="left">N.D.</td><td align="left">N.D.</td></tr></tbody></table><table-wrap-foot><fn><p>N.D. Not determined.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tbl1fna"><label>a</label><p id="ntpara0010">CC<sub>50</sub> was determined with serially-diluted compounds in Vero E6 cells at 48 h post-incubation using CellTiter-Glow Luminescent Cell Viability Assay (Promega).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tbl1fnb"><label>b</label><p id="ntpara0015">Compounds were serially 2-fold or 4-fold diluted from 100 μM, except ribavirin which was started at 500 μM. Cytopathic effects (CPE) of SARS-CoV-2 virus in Vero E6 cells under increasing concentration of the compounds were observed at 48 h post-infection. The lowest concentration of the compound with 100% CPE inhibition (eg. exhibiting comparable CPE of non-infected controls) was recorded.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tbl1fnc"><label>c</label><p id="ntpara0020">EC<sub>50</sub> determined by infectious virus yield in culture supernatant at 48h post-infection (log<sub>10</sub> TCID<sub>50</sub>/mL).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tbl1fnd"><label>d</label><p id="ntpara0025">EC<sub>50</sub> determined by viral RNA copy numbers in culture supernatant at 48h post-infection (log<sub>10</sub> RNA copies/mL).</p></fn></table-wrap-foot></table-wrap><fig id="fig1"><label>Fig. 1</label><caption><p><bold>Antiviral activity of remdesivir (A), lopinavir (B), homorringtonine (C) and emetine dihydrochloride (D) against SARS-CoV-2 virus in vitro.</bold> Infectious viral loads (log<sub>10</sub>TCID<sub>50</sub>/mL left Y axis) and viability (normalized to the ATP level of the Vero E6 cells incubated with infection media) under increasing concentrations of the antiviral compounds are shown.</p></caption><alt-text id="alttext0010">Fig. 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="p0050">Lopinavir in combination with ritonavir are FDA approved HIV-1 protease inhibitors. Lopinavir was more potent in inhibiting HIV-1 than ritonavir in vitro but showed poor bioavailability in vivo. Ritonavir inhibits not only HIV-1 protease but also the host's cytochrome P450 3A4 enzyme that metabolizes lopinavir (<xref rid="bib18" ref-type="bibr">Kempf et al., 1997</xref>). Lopinavir/ritonavir in combination prolongs bioavailability of lopinavir in vivo (<xref rid="bib28" ref-type="bibr">Sham et al., 1998</xref>). Lopinavir but not ritonavir showed antiviral effect against SARS-CoV, MERS-CoV, and hCoV-229E in vitro, with mean EC<sub>50</sub> ranged from 6.6 to 17.1 μM (<xref rid="bib11" ref-type="bibr">de Wilde et al., 2014</xref>). Lopinavir/ritonavir in combination with ribavirin were used previously to treat SARS-CoV patients under a non-randomized clinical trial. Less SARS patients developed into ARDS or death after receiving the combination of lopinavir/ritonavir with ribavirin than historical controls who received ribavirin and corticosteroids (<xref rid="bib9" ref-type="bibr">Chu et al., 2004</xref>). Efficacy of lopinavir/ritonavir with or without ribavirin is currently evaluated in SARS-CoV-2 patients under randomized control trials. In agreement with previous reports, we observed antiviral effect of lopinavir (EC<sub>50</sub> at 26.1 μM) but not ritonavir against SARS-CoV-2 in vitro (<xref rid="fig1" ref-type="fig">Fig. 1</xref>B and <xref rid="tbl1" ref-type="table">Table 1</xref>). HIV-1 patients treated with 400 mg of lopinavir and 100 mg of ritonavir twice daily may reach the minimal lopinavir serum concentration at 9.4 μM (IQR 7.2–12.1 μM), which is below the EC<sub>50</sub> against SARS-CoV-2 virus in vitro (<xref rid="bib21" ref-type="bibr">Lopez-Cortes et al., 2013</xref>). Currently, lopinavir/ritonavir at 400mg/100 mg twice daily with or without ribavirin are part of the recommended treatment for managing COVID-19 patients in China (<xref rid="bib7" ref-type="bibr">China National Health Commission, 2020</xref>). A recent randomized control trial reported no significant benefit of lopinavir-ritonavir in hospitalized SARS-CoV-2 patients than standard care, as the time to clinical improvement, mortality at 28 days, and viral loads at various time points were comparable between the two groups (<xref rid="bib5" ref-type="bibr">Cao et al., 2020</xref>). Combinational therapy of lopinavir with the other effective compounds against SARS-CoV-2 virus may increase synergy and reduce the inhibitory concentration of lopinavir.</p><p id="p0055">Homoharringtonine is a plant alkaloid derived from <italic>Cephalotoxus fortunei</italic>. It exhibits anti-tumor activity by binding to the ribosomal A site to inhibit protein translation, leading to rapid loss of short-lived proteins including Mcl-1 and c-Myc that promote the survival of leukemia cells (<xref rid="bib13" ref-type="bibr">Dong et al., 2018</xref>; <xref rid="bib22" ref-type="bibr">Lu and Wang, 2014</xref>). Omacetaxine, a semi-synthetic form of homoharringtonine, is approved by FDA for treatment of chronic myeloid leukemia. Homoharringtonine has also been reported to exhibit potent anti-viral activity against herpesviruses (varicella-zoster virus, herpes simplex virus-1, pseudorabies virus), coronaviruses (porcine epidemic diarrhea virus and murine hepatitis virus), rhabdoviruses (VSV and rabies virus), and other viruses (hepatitis B virus, Newcastle disease virus, and echovirus 1) (<xref rid="bib13" ref-type="bibr">Dong et al., 2018</xref>; <xref rid="bib2" ref-type="bibr">Andersen et al., 2019</xref>). Here, we observed homoharringtonine inhibits SARS-CoV-2 with EC<sub>50</sub> at 2.10 μM (<xref rid="fig1" ref-type="fig">Fig. 1</xref>C and <xref rid="tbl1" ref-type="table">Table 1</xref>). Previous pharmacokinetic study showed that patients treated with 1.25 mg/m<sup>2</sup> omacetaxine every 12 h by subcutaneous injection may reach the maximal plasma concentration at 25.1 ng/mL (0.046 μM) and 36.2 ng/mL (0.066 μM) on days 1 and 11, respectively (<xref rid="bib26" ref-type="bibr">Nemunaitis et al., 2013</xref>), which were below the EC<sub>50</sub> against SARS-CoV-2 virus in vitro.</p><p id="p0060">Emetine is a protein synthesis inhibitor that was used as anti-protozoan approved for treatment of ameobiasis; it also inhibits malaria by binding to the ribosomal E site of <italic>Plasmodium falciparum</italic> (<xref rid="bib16" ref-type="bibr">Grollman, 1966</xref>; <xref rid="bib33" ref-type="bibr">Wong et al., 2014</xref>). However, its potential cardiotoxicity has restricted its clinical use in the recent years. It was found to process antiviral activity against a broad range of RNA and DNA viruses, including Zika virus, Ebolavirus, Cytomegalovirus, rabies virus, HIV-1, echovirus 1, buffalo poxvirus, bovine herpesvirus 1, peste des petits ruminants virus, Newcastle disease virus, herpes simplex virus-2, metapneumovirus, Rift Valley fever virus, and influenza (<xref rid="bib2" ref-type="bibr">Andersen et al., 2019</xref>; <xref rid="bib6" ref-type="bibr">Chaves Valadao et al., 2015</xref>; <xref rid="bib19" ref-type="bibr">Khandelwal et al., 2017</xref>; <xref rid="bib23" ref-type="bibr">MacGibeny et al., 2018</xref>; <xref rid="bib25" ref-type="bibr">Mukhopadhyay et al., 2016</xref>; <xref rid="bib36" ref-type="bibr">Yang et al., 2018</xref>). Emetine was also identified to inhibit hCoV-OC43, hCoV-NL43, SARS-CoV, MERS-CoV, and MHV-A59 in vitro with EC<sub>50</sub> reported at low micromolar range (<xref rid="bib14" ref-type="bibr">Dyall et al., 2014</xref>; <xref rid="bib30" ref-type="bibr">Shen et al., 2019</xref>). We observed emetine at around 0.5 μM may effectively inhibit SARS-CoV-2 virus replication (<xref rid="fig1" ref-type="fig">Fig. 1</xref>D and <xref rid="tbl1" ref-type="table">Table 1</xref>). The therapeutic plasma concentration of emetine may reach 0.075 μg/mL (0.156 μM) (<xref rid="bib27" ref-type="bibr">Regenthal et al., 1999</xref>), which is below the EC<sub>50</sub> against SARS-CoV-2 virus in vitro. The toxic plasma concentration is 0.5 μg/mL (1.04 μM) (<xref rid="bib27" ref-type="bibr">Regenthal et al., 1999</xref>).</p><p id="p0065">To reduce the effective concentration of individual compound below the maximal therapeutic plasma concentration, we explored the combinational effect of remdesivir and emetine in vitro. Drug interaction was evaluated using the checkerboard assay with serially 2-fold diluted remdesivir (0–50 μM) and emetine (0–0.781 μM) in combination. Remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition of viral yield, which can be further tested in vivo (<xref rid="fig2" ref-type="fig">Fig. 2</xref>A). The Loewe additive model and the Bliss independent model (<xref rid="bib24" ref-type="bibr">Malyutina et al., 2019</xref>) were used to analyse the interaction of the two compounds using SynergyFinder (<xref rid="bib17" ref-type="bibr">Ianevski et al., 2017</xref>). Remdesivir and emetine in combination yielded a Loewe synergy score of 0.306 (<xref rid="fig2" ref-type="fig">Fig. 2</xref>B) and a Bliss synergy score of 20.234 (<xref rid="fig2" ref-type="fig">Fig. 2</xref>C).<fig id="fig2"><label>Fig. 2</label><caption><p><bold>Combinational effect of remdesivir and emetine dihydrochloride against SARS-CoV-2 virus in vitro.</bold> (A) Dose response matrix of serially 2-fold diluted remdesivir (0–50 μM) and emetine (0–0.781 μM) in Vero E6 cells. The percentage of viral inhibition was normalized based on viral load in logarithm scale (log<sub>10</sub>RNA copies/mL), using the maximal viral RNA copies with no drug controls as 0% inhibition and the minimal RNA copies determined at 50 μM remdesivir as references. (B) The three-dimensional interaction landscapes of remdesivir and emetine were generated by SynergyFinder (<xref rid="bib17" ref-type="bibr">Ianevski et al., 2017</xref>) based on (B) the Loewe additive model and (C) the Bliss independence model. Red colour indicates synergy while the green colour indicates antagonism of the two drugs.</p></caption><alt-text id="alttext0015">Fig. 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig></p><p id="p0070">We confirm the antiviral activity of four compounds that have been reported to inhibit other coronavirus or SARS-CoV-2 replication in vitro. Our results suggest that combinational therapy may help to reduce the effective concentration against SARS-CoV-2 under the maximal therapeutic plasma concentration. 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