Enisamium Inhibits SARS-CoV-2 RNA Synthesis
Stefano Elli, Denisa Bojkova, Marco Bechtel, Thomas Vial, David Boltz, Miguel Muzzio, Xinjian Peng, Federico Sala, Cesare Cosentino, Andrew Goy, Marco Guerrini, Lutz Müller, Jindrich Cinatl, Victor Margitich, Aartjan J W Te Velthuis
Biomedicines, doi:10.3390/biomedicines9091254
Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 . While control of the SARS-CoV-2 spread partly depends on vaccineinduced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro.
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the Treatment of Covid-19-Final Report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764Bojkova, Bechtel, Mclaughlin, Mcgreig, Klann et al., Aprotinin Inhibits SARS-CoV-2 Replication, Cells,
doi:10.3390/cells9112377Bojkova, Klann, Koch, Widera, Krause et al., Proteomics of SARS-CoV-2-infected host cells reveals therapy targets, Nature,
doi:10.1038/s41586-020-2332-7Boltz, Peng, Muzzio, Dash, Thomas et al., Activity of enisamium, an isonicotinic acid derivative, against influenza viruses in differentiated normal human bronchial epithelial cells, Antivir Chem. Chemother,
doi:10.1177/2040206618811416Case, Cheatham, Darden, Gohlke, Luo et al., The Amber biomolecular simulation programs, J. Comput. Chem,
doi:10.1002/jcc.20290Chen, Malone, Llewellyn, Grasso, Shelton et al., Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex, Cell,
doi:10.1016/j.cell.2020.07.033Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat. Microbiol,
doi:10.1038/s41564-020-00835-2Frisch, Trucks, Schlegel, Scuseria, Robb et al., Revision C.01
Goldhill, .; Te, Velthuis, Fletcher, Langat et al., The mechanism of resistance to favipiravir in influenza, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1811345115Jorgensen, Chandrasekhar, Madura, Impey, Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys,
doi:10.1063/1.445869Morris, Huey, Lindstrom, Sanner, Belew et al., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J. Comput. Chem,
doi:10.1002/jcc.21256Phillips, Braun, Wang, Gumbart, Tajkhorshid et al., Scalable molecular dynamics with NAMD, J. Comput. Chem,
doi:10.1002/jcc.20289Shannon, Selisko, Le, Huchting, Touret et al., Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis, Nat. Commun,
doi:10.1038/s41467-020-18463-zSheahan, Sims, Zhou, Graham, Pruijssers et al., An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice, Sci. Transl. Med,
doi:10.1126/scitranslmed.abb5883Srinivasan, Cheatham, Iii; Cieplak, Kollman, Case, Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices, J. Am. Chem. Soc,
doi:10.1021/ja981844+Subissi, Imbert, Ferron, Collet, Coutard et al., SARS-CoV ORF1b-encoded nonstructural proteins 12-16: Replicative enzymes as antiviral targets, Antivir. Res,
doi:10.1016/j.antiviral.2013.11.006Subissi, Posthuma, Collet, Zevenhoven-Dobbe, Gorbalenya et al., One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.1323705111Toptan, Hoehl, Westhaus, Bojkova, Berger et al., Optimized qRT-PCR Approach for the Detection of Intra-and Extra-Cellular SARS-CoV-2 RNAs, Int. J. Mol. Sci,
doi:10.3390/ijms21124396Velthuis, Arnold, Cameron, Van Den Worm, Snijder, The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent, Nucleic Acids Res,
doi:10.1093/nar/gkp904Velthuis, Zubkova, Shaw, Mehle, Boltz et al., Enisamium Reduces Influenza Virus Shedding and Improves Patient Recovery by Inhibiting Viral RNA Polymerase Activity, Antimicrob Agents Chemother,
doi:10.1128/AAC.02605-20Vial, Oade, Russell, Eggink, Velthuis, A SARS-CoV-2 mini-genome assay based on negative-sense RNA to study replication inhibitors and emerging mutations, BioRxiv,
doi:10.1101/2021.06.28.450211Walker, Fan, Keown, Margitich, Grimes et al., Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases, bioRxiv,
doi:10.1101/2020.04.21.053017Weis, Katebzadeh, Söderhjelm, Nilsson, Ryde, Ligand affinities predicted with the MM/PBSA method: Dependence on the simulation method and the force field, J. Med. Chem,
doi:10.1021/jm0608210Yan, Zhang, Ge, Zheng, Gao et al., Architecture of a SARS-CoV-2 mini replication and transcription complex, Nat. Commun,
doi:10.1038/s41467-020-19770-1Yin, Mao, Luan, Shen, Shen et al., Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir, Science,
doi:10.1126/science.abc1560Zurbaev, Slita, Sinegubova, Muryleva, Lavrentieva, Anti-viral activity of enisamium iodide against viruses of influenza and ARVI's on different cell lines, Ther. Arch,
doi:10.26442/00403660.2020.11.000872DOI record:
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"abstract": "<jats:p>Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called coronavirus disease 2019 (COVID-19). While control of the SARS-CoV-2 spread partly depends on vaccine-induced or naturally acquired protective herd immunity, antiviral strategies are still needed to manage COVID-19. Enisamium is an inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. In vitro, enisamium acts through metabolite VR17-04 and inhibits the activity of the influenza A virus RNA polymerase. Here we show that enisamium can inhibit coronavirus infections in NHBE and Caco-2 cells, and the activity of the SARS-CoV-2 RNA polymerase in vitro. Docking and molecular dynamics simulations provide insight into the mechanism of action and indicate that enisamium metabolite VR17-04 prevents GTP and UTP incorporation. Overall, these results suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis in vitro.</jats:p>",
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"DOI": "10.1038/s41467-020-18463-z",
"article-title": "Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis",
"author": "Shannon",
"doi-asserted-by": "crossref",
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"journal-title": "Nat. Commun.",
"key": "ref_3",
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},
{
"DOI": "10.1073/pnas.1811345115",
"article-title": "The mechanism of resistance to favipiravir in influenza",
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"first-page": "11613",
"journal-title": "Proc. Natl. Acad. Sci. USA",
"key": "ref_4",
"volume": "115",
"year": "2018"
},
{
"DOI": "10.1074/jbc.REV120.013930",
"article-title": "The molecular virology of coronaviruses",
"author": "Hartenian",
"doi-asserted-by": "crossref",
"first-page": "12910",
"journal-title": "J. Biol. Chem.",
"key": "ref_5",
"volume": "295",
"year": "2020"
},
{
"DOI": "10.1038/s41564-020-0695-z",
"doi-asserted-by": "crossref",
"key": "ref_6",
"unstructured": "Coronaviridae Study Group of the International Committee on Taxonomy of V (2020). The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol., 5, 536–544."
},
{
"DOI": "10.1016/j.antiviral.2013.11.006",
"article-title": "SARS-CoV ORF1b-encoded nonstructural proteins 12-16: Replicative enzymes as antiviral targets",
"author": "Subissi",
"doi-asserted-by": "crossref",
"first-page": "122",
"journal-title": "Antivir. Res.",
"key": "ref_7",
"volume": "101",
"year": "2014"
},
{
"DOI": "10.1093/nar/gkp904",
"article-title": "The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent",
"author": "Arnold",
"doi-asserted-by": "crossref",
"first-page": "203",
"journal-title": "Nucleic Acids Res.",
"key": "ref_8",
"volume": "38",
"year": "2010"
},
{
"DOI": "10.1073/pnas.1323705111",
"article-title": "One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities",
"author": "Subissi",
"doi-asserted-by": "crossref",
"first-page": "E3900",
"journal-title": "Proc. Natl. Acad. Sci. USA",
"key": "ref_9",
"volume": "111",
"year": "2014"
},
{
"DOI": "10.1038/s41467-020-19770-1",
"article-title": "Architecture of a SARS-CoV-2 mini replication and transcription complex",
"author": "Yan",
"doi-asserted-by": "crossref",
"first-page": "5874",
"journal-title": "Nat. Commun.",
"key": "ref_10",
"volume": "11",
"year": "2020"
},
{
"DOI": "10.1038/s41586-020-2368-8",
"article-title": "Structure of replicating SARS-CoV-2 polymerase",
"author": "Hillen",
"doi-asserted-by": "crossref",
"first-page": "154",
"journal-title": "Nature",
"key": "ref_11",
"volume": "584",
"year": "2020"
},
{
"DOI": "10.1016/j.cell.2020.07.033",
"article-title": "Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex",
"author": "Chen",
"doi-asserted-by": "crossref",
"first-page": "1560",
"journal-title": "Cell",
"key": "ref_12",
"volume": "182",
"year": "2020"
},
{
"DOI": "10.1128/AAC.02605-20",
"doi-asserted-by": "crossref",
"key": "ref_13",
"unstructured": "Te Velthuis, A.J.W., Zubkova, T.G., Shaw, M., Mehle, A., Boltz, D., Gmeinwieser, N., Stammer, H., Milde, J., Muller, L., and Margitich, V. (2021). Enisamium Reduces Influenza Virus Shedding and Improves Patient Recovery by Inhibiting Viral RNA Polymerase Activity. Antimicrob Agents Chemother, 65."
},
{
"DOI": "10.1101/2021.06.28.450211",
"doi-asserted-by": "crossref",
"key": "ref_14",
"unstructured": "Vial, T., Oade, M.S., Russell, C.A., Eggink, D., and te Velthuis, A.J.W. (2021). A SARS-CoV-2 mini-genome assay based on negative-sense RNA to study replication inhibitors and emerging mutations. BioRxiv."
},
{
"DOI": "10.1101/2020.04.21.053017",
"doi-asserted-by": "crossref",
"key": "ref_15",
"unstructured": "Walker, A.P., Fan, H., Keown, J.R., Margitich, V., Grimes, J.M., Fodor, E., and Te Velthuis, A.J.W. (2021). Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases. bioRxiv."
},
{
"DOI": "10.1056/NEJMoa2007764",
"article-title": "Remdesivir for the Treatment of Covid-19—Final Report",
"author": "Beigel",
"doi-asserted-by": "crossref",
"first-page": "1813",
"journal-title": "N. Engl. J. Med.",
"key": "ref_16",
"volume": "383",
"year": "2020"
},
{
"DOI": "10.1177/2040206618811416",
"article-title": "Activity of enisamium, an isonicotinic acid derivative, against influenza viruses in differentiated normal human bronchial epithelial cells",
"author": "Boltz",
"doi-asserted-by": "crossref",
"first-page": "2040206618811416",
"journal-title": "Antivir Chem. Chemother.",
"key": "ref_17",
"volume": "26",
"year": "2018"
},
{
"DOI": "10.26442/00403660.2020.11.000872",
"article-title": "Anti-viral activity of enisamium iodide against viruses of influenza and ARVI’s on different cell lines",
"author": "Zurbaev",
"doi-asserted-by": "crossref",
"first-page": "45",
"journal-title": "Ther. Arch.",
"key": "ref_18",
"volume": "92",
"year": "2020"
},
{
"DOI": "10.1038/s41586-020-2332-7",
"article-title": "Proteomics of SARS-CoV-2-infected host cells reveals therapy targets",
"author": "Bojkova",
"doi-asserted-by": "crossref",
"first-page": "469",
"journal-title": "Nature",
"key": "ref_19",
"volume": "583",
"year": "2020"
},
{
"DOI": "10.3390/cells9112377",
"doi-asserted-by": "crossref",
"key": "ref_20",
"unstructured": "Bojkova, D., Bechtel, M., McLaughlin, K.M., McGreig, J.E., Klann, K., Bellinghausen, C., Rohde, G., Jonigk, D., Braubach, P., and Ciesek, S. (2020). Aprotinin Inhibits SARS-CoV-2 Replication. Cells, 9."
},
{
"DOI": "10.1101/2020.04.20.052258",
"doi-asserted-by": "crossref",
"key": "ref_21",
"unstructured": "Toptan, T., Hoehl, S., Westhaus, S., Bojkova, D., Berger, A., Rotter, B., Hoffmeier, K., Cinatl, J., Ciesek, S., and Widera, M. (2020). Optimized qRT-PCR Approach for the Detection of Intra- and Extra-Cellular SARS-CoV-2 RNAs. Int. J. Mol. Sci., 21."
},
{
"key": "ref_22",
"unstructured": "Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Revision C.01, Gaussian Inc."
},
{
"DOI": "10.1002/jcc.21256",
"article-title": "AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility",
"author": "Morris",
"doi-asserted-by": "crossref",
"first-page": "2785",
"journal-title": "J. Comput. Chem.",
"key": "ref_23",
"volume": "30",
"year": "2009"
},
{
"DOI": "10.1126/science.abc1560",
"article-title": "Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir",
"author": "Yin",
"doi-asserted-by": "crossref",
"first-page": "1499",
"journal-title": "Science",
"key": "ref_24",
"volume": "368",
"year": "2020"
},
{
"DOI": "10.1016/0040-4020(80)80168-2",
"article-title": "Iterative partial equalization of orbital electronegativity a rapid access to atomic charges",
"author": "Gesteiger",
"doi-asserted-by": "crossref",
"first-page": "3219",
"journal-title": "Tetrahedron",
"key": "ref_25",
"volume": "36",
"year": "1980"
},
{
"DOI": "10.1002/jcc.20289",
"article-title": "Scalable molecular dynamics with NAMD",
"author": "Phillips",
"doi-asserted-by": "crossref",
"first-page": "1781",
"journal-title": "J. Comput. Chem.",
"key": "ref_26",
"volume": "26",
"year": "2005"
},
{
"DOI": "10.1002/jcc.20290",
"article-title": "The Amber biomolecular simulation programs",
"author": "Case",
"doi-asserted-by": "crossref",
"first-page": "1668",
"journal-title": "J. Comput. Chem.",
"key": "ref_27",
"volume": "26",
"year": "2005"
},
{
"DOI": "10.1063/1.445869",
"article-title": "Comparison of simple potential functions for simulating liquid water",
"author": "Jorgensen",
"doi-asserted-by": "crossref",
"first-page": "926",
"journal-title": "J. Chem. Phys.",
"key": "ref_28",
"volume": "79",
"year": "1983"
},
{
"DOI": "10.1016/0263-7855(96)00018-5",
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"author": "Humphrey",
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"first-page": "27",
"journal-title": "J. Mol. Graph.",
"key": "ref_29",
"volume": "14",
"year": "1996"
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"DOI": "10.1021/jm0608210",
"article-title": "Ligand affinities predicted with the MM/PBSA method: Dependence on the simulation method and the force field",
"author": "Weis",
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"first-page": "6596",
"journal-title": "J. Med. Chem.",
"key": "ref_30",
"volume": "49",
"year": "2006"
},
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"DOI": "10.1021/ja981844+",
"article-title": "Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate–DNA helices",
"author": "Srinivasan",
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"first-page": "9401",
"journal-title": "J. Am. Chem. Soc.",
"key": "ref_31",
"volume": "120",
"year": "1998"
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"title": "Enisamium Inhibits SARS-CoV-2 RNA Synthesis",
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