The antiviral compound remdesivir potently inhibits RNAdependent RNA polymerase from Middle East respiratory syndrome coronavirus

Journal of Biological Chemistry

Volumn 295, Issue 15, 2020, Pages 4773-4779

  Gordon, Calvin J ^a   Tchesnokov, Egor P ^a   Feng, Joy Y ^c   Porter, Danielle P ^c   Götte, Matthias ^a,b  

^a UNIVERSITY OF ALBERTA   (Canada)

^b UNIVERSITY OF ALBERTA   (Canada)

^c GILEAD SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DISEASES; NUCLEOTIDES; VIRUSES;

ANTIVIRAL ACTIVITIES; CHAIN TERMINATIONS; EXONUCLEASE ACTIVITY; MECHANISM OF ACTION; NONSTRUCTURAL PROTEINS; RNA-DEPENDENT RNA POLYMERASE; SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS; SEVERE ACUTE RESPIRATORY SYNDROME COV;

RNA;

ADENOSINE TRIPHOSPHATE; NONSTRUCTURAL PROTEIN 5; NONSTRUCTURAL PROTEIN 7; NUCLEOTIDE; PHOSPHODIESTERASE I; REMDESIVIR; RNA DIRECTED RNA POLYMERASE; SPLEEN EXONUCLEASE; UNCLASSIFIED DRUG; VIRAL PROTEIN; ADENOSINE PHOSPHATE; ALANINE; ANTIVIRUS AGENT; NUCLEIC ACID SYNTHESIS INHIBITOR; PRIMER RNA; RNA;

ANTIVIRAL ACTIVITY; CONTROLLED STUDY; DNA SEQUENCE; DRUG MECHANISM; ENZYME ACTIVITY; ENZYME INHIBITION; IC50; LIMIT OF QUANTITATION; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; RNA SYNTHESIS; SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2; ANIMAL; CHEMISTRY; CORONAVIRINAE; DRUG EFFECT; EBOLAVIRUS; ENZYMOLOGY; GENE EXPRESSION; GENETICS; SF9 CELL LINE; VIRUS REPLICATION;

ADENOSINE MONOPHOSPHATE; ALANINE; ANIMALS; ANTIVIRAL AGENTS; CORONAVIRUS; EBOLAVIRUS; GENE EXPRESSION; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; NUCLEIC ACID SYNTHESIS INHIBITORS; RNA; RNA-DEPENDENT RNA POLYMERASE; SF9 CELLS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 85082692157     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.AC120.013056     Document Type: Review

References (26)

1. Sheahan, T. P., Sims, A. C., Leist, S. R., Schäfer, A., Won, J., Brown, A. J., Montgomery, S. A., Hogg, A., Babusis, D., Clarke, M. O., Spahn, J. E., Bauer, L., Sellers, S., Porter, D., Feng, J. Y., et al. (2020) Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon β against MERS-CoV. Nat. Commun. 11, 222 CrossRef Medline
2. Siegel, D., Hui, H. C., Doerffler, E., Clarke, M. O., Chun, K., Zhang, L., Neville, S., Carra, E., Lew, W., Ross, B., Wang, Q., Wolfe, L., Jordan, R., Soloveva, V., Knox, J., et al. (2017) Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2, 1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J. Med. Chem. 60, 1648-1661 CrossRef Medline
3. Lo, M. K., Jordan, R., Arvey, A., Sudhamsu, J., Shrivastava-Ranjan, P., Hotard, A. L., Flint, M., McMullan, L. K., Siegel, D., Clarke, M. O., Mackman, R. L., Hui, H. C., Perron, M., Ray, A. S., Cihlar, T., et al. (2017) GS-5734 and its parent nucleoside analog inhibit filo-, pneumo-, and paramyxoviruses. Sci. Rep. 7, 43395 CrossRef Medline
4. Warren, T. K., Jordan, R., Lo, M. K., Ray, A. S., Mackman, R. L., Soloveva, V., Siegel, D., Perron, M., Bannister, R., Hui, H. C., Larson, N., Strickley, R., Wells, J., Stuthman, K. S., Van Tongeren, S. A., et al. (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531, 381-385 CrossRef Medline
5. Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., et al. (2018) Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio 9, e00221-18 Medline
6. Brown, A. J., Won, J. J., Graham, R. L., Dinnon, K. H., 3rd, Sims, A. C., Feng, J. Y., Cihlar, T., Denison, M. R., Baric, R. S., and Sheahan, T. P. (2019) Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 169, 104541 CrossRef Medline
7. Jordan, P. C., Liu, C., Raynaud, P., Lo, M. K., Spiropoulou, C. F., Symons, J. A., Beigelman, L., and Deval, J. (2018) Initiation, extension, and termination ofRNAsynthesis by a paramyxovirus polymerase. PLoS Pathog. 14, e1006889 CrossRef Medline
8. Tchesnokov, E. P., Feng, J. Y., Porter, D. P., and Götte, M. (2019) Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses 11, E326 Medline
9. Mühlberger, E., Weik, M., Volchkov, V. E., Klenk, H. D., and Becker, S. (1999) Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J. Virol. 73, 2333-2342 CrossRef Medline
10. Tchesnokov, E. P., Raeisimakiani, P., Ngure, M., Marchant, D., and Götte, M. (2018) Recombinant RNA-dependent RNA polymerase complex of Ebola virus. Sci. Rep. 8, 3970 CrossRef Medline
11. Deval, J., Hong, J., Wang, G., Taylor, J., Smith, L. K., Fung, A., Stevens, S. K., Liu, H., Jin, Z., Dyatkina, N., Prhavc, M., Stoycheva, A. D., Serebryany, V., Liu, J., Smith, D. B., et al. (2015) Molecular basis for the selective inhibition of respiratory syncytial virus RNA polymerase by 2'-fluoro-4'-chloromethyl-cytidine triphosphate. PLoS Pathog. 11
12. Noton, S. L., Deflubé, L. R., Tremaglio, C. Z., and Fearns, R. (2012) The respiratory syncytial virus polymerase has multiple RNA synthesis activities at the promoter. PLoS Pathog. 8, e1002980 CrossRef Medline
13. Kirchdoerfer, R. N., and Ward, A. B. (2019) Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat. Commun. 10, 2342 CrossRef Medline
14. Ferron, F., Subissi, L., Silveira De Morais, A. T., Le, N. T. T., Sevajol, M., Gluais, L., Decroly, E., Vonrhein, C., Bricogne, G., Canard, B., and Imbert, I. (2018) Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc. Natl. Acad. Sci. U.S.A. 115, E162-E171 CrossRef Medline
15. Subissi, L., Posthuma, C. C., Collet, A., Zevenhoven-Dobbe, J. C., Gorbalenya, A. E., Decroly, E., Snijder, E. J., Canard, B., and Imbert, I. (2014) One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc. Natl. Acad. Sci. U.S.A. 111, E3900-E3909 CrossRef Medline
16. Poch, O., Sauvaget, I., Delarue, M., and Tordo, N. (1989) Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J. 8, 3867-3874 CrossRef Medline
17. Imbert, I., Guillemot, J. C., Bourhis, J. M., Bussetta, C., Coutard, B., Egloff, M. P., Ferron, F., Gorbalenya, A. E., and Canard, B. (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J. 25, 4933-4942 CrossRef Medline
18. Mulangu, S., Dodd, L. E., Davey, R. T., Jr., Tshiani Mbaya, O., Proschan, M., Mukadi, D., Lusakibanza Manzo, M., Nzolo, D., Tshomba Oloma, A., Ibanda, A., Ali, R., Coulibaly, S., Levine, A. C., Grais, R., Diaz, J., et al. (2019) A randomized, controlled trial of Ebola virus disease therapeutics. New Engl. J. Med. 381, 2293-2303 CrossRef Medline
19. Sheahan, T. P., Sims, A. C., Graham, R. L., Menachery, V. D., Gralinski, L. E., Case, J. B., Leist, S. R., Pyrc, K., Feng, J. Y., Trantcheva, I., Bannister, R., Park, Y., Babusis, D., Clarke, M. O., Mackman, R. L., et al. (2017) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 9, eaal3653 CrossRef Medline
20. de Wit, E., Feldmann, F., Cronin, J., Jordan, R., Okumura, A., Thomas, T., Scott, D., Cihlar, T., and Feldmann, H. (2020) Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc. Natl. Acad. Sci. U.S.A. 201922083 CrossRef Medline
21. de Wilde, A. H., Jochmans, D., Posthuma, C. C., Zevenhoven-Dobbe, J. C., van Nieuwkoop, S., Bestebroer, T. M., van den Hoogen, B. G., Neyts, J., and Snijder, E. J. (2014) Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 58, 4875-4884 CrossRef Medline
22. Arabi, Y. M., Asiri, A. Y., Assiri, A. M., Aziz Jokhdar, H. A., Alothman, A., Balkhy, H. H., AlJohani, S., Al Harbi, S., Kojan, S., Al Jeraisy, M., Deeb, A. M., Memish, Z. A., Ghazal, S., Al Faraj, S., Al-Hameed, F., et al. (2020) Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): Statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials 21, 8 CrossRef Medline
23. Tchesnokov, E. P., Obikhod, A., Schinazi, R. F., and Götte, M. (2008) Delayed chain termination protects the anti-hepatitis B virus drug entecavir from excision by HIV-1 reverse transcriptase. J. Biol. Chem. 283, 34218-34228 CrossRef Medline
24. Dulin, D., Arnold, J. J., van Laar, T., Oh, H. S., Lee, C., Perkins, A. L., Harki, D. A., Depken, M., Cameron, C. E., and Dekker, N. H. (2017) Signatures of nucleotide analog incorporation by an RNA-dependent RNA polymerase revealed using high-throughput magnetic tweezers. Cell Reports 21, 1063-1076 CrossRef Medline
25. Berger, I., Fitzgerald, D. J., and Richmond, T. J. (2004) Baculovirus expression system for heterologous multiprotein complexes. Nat. Biotechnol. 22, 1583-1587 CrossRef Medline
26. Bieniossek, C., Richmond, T. J., and Berger, I. (2008) MultiBac: Multigene baculovirus-based eukaryotic protein complex production. Curr. Protoc. Protein Sci. Chapter 5, Unit 5.20 CrossRef Medline