Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

mBio

Volumn 9, Issue 2, 2018, Pages

  Agostini, Maria L ^a   Andres, Erica L ^b   Sims, Amy C ^c   Graham, Rachel L ^c   Sheahan, Timothy P ^c   Lu, Xiaotao ^b   Smith, Everett Clinton ^b,d   Case, James Brett ^a   Feng, Joy Y ^e   Jordan, Robert ^e   Ray, Adrian S ^e   Cihlar, Tomas ^e   Siegel, Dustin ^e   Mackman, Richard L ^e   Clarke, Michael O ^e   Baric, Ralph S ^c   Denison, Mark R ^a,b  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^c IL   (United States)

^d UNIVERSITY OF THE SOUTH   (United States)

^e GILEAD SCIENCES   (United States)

Author keywords

Antiviral agents; Antiviral resistance; Coronavirus; Nucleoside analogs; Pandemic; RNA polymerases; SARS CoV

Indexed keywords

EXORIBONUCLEASE; NSP12 PROTEIN; REMDESIVIR; UNCLASSIFIED DRUG; VIRAL POLYMERASE; VIRUS ENZYME; ALANINE; ANTIVIRUS AGENT; GS-5734; RIBONUCLEOTIDE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL RESISTANCE; ANTIVIRAL SUSCEPTIBILITY; ARTICLE; CONTROLLED STUDY; CORONAVIRINAE; EC50; HUMAN; HUMAN CELL; IN VITRO STUDY; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; MIXED INFECTION; MOUSE; MOUSE MODEL; MURINE HEPATITIS VIRUS; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; SARS CORONAVIRUS; VIRUS MUTATION; ANALOGS AND DERIVATIVES; ANIMAL; CHEMISTRY; DRUG EFFECT; ENZYMOLOGY; GENETICS; METABOLISM; MUTATION; VIRUS REPLICATION;

ALANINE; ANIMALS; ANTIVIRAL AGENTS; CORONAVIRUS; EXORIBONUCLEASES; MICE; MUTATION; RIBONUCLEOTIDES; SARS VIRUS; VIRUS REPLICATION;

EID: 85046493350     PISSN: 21612129     EISSN: 21507511     Source Type: Journal    
DOI: 10.1128/mBio.00221-18     Document Type: Article

References (58)

1. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling A, Humphrey CD, Shieh W, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang J, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ. 2003. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 348:1953-1966. https://doi.org/10.1056/NEJMoa030781.
2. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367:1814-1820. https://doi.org/10.1056/ NEJMoa1211721.
3. Chan-Yeung M, Xu RH. 2003. SARS: epidemiology. Respirology 8((Suppl)):S9-S14. https://doi.org/10.1046/j.1440-1843.2003.00518.x.
4. Stockman LJ, Bellamy R, Garner P. 2006. SARS: systematic review of treatment effects. PLoS Med 3:e343. https://doi.org/10.1371/journal.pmed.0030343.
5. Cheng VCC, Lau SKP, Woo PCY, Yuen KY. 2007. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 20:660-694. https://doi.org/10.1128/CMR.00023-07.
6. Cheng VCC, Chan JFW, To KKW, Yuen KY. 2013. Clinical management and infection control of SARS: lessons learned. Antiviral Res 100:407-419. https://doi.org/10.1016/j.antiviral.2013.08.016.
7. Zumla A, Chan JFW, Azhar EI, Hui DSC, Yuen KY. 2016. Coronaviruses-drug discovery and therapeutic options. Nat Rev Drug Discov 15:327-347. https://doi.org/10.1038/nrd.2015.37.
8. Chan JFW, Lau SKP, To KKW, Cheng VCC, Woo PCY, Yuen KY. 2015. Middle East respiratory syndrome coronavirus: another zoonotic Betacoronavirus causing SARS-like disease. Clin Microbiol Rev 28:465-522. https://doi.org/10.1128/CMR.00102-14.
9. Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, Al-Omari A, Hajeer AH, Senga M, Denison MR, Nguyen-Van-Tam JS, Shindo N, Bermingham A, Chappell JD, Van Kerkhove MD, Fowler RA. 2017. Middle East respiratory syndrome. N Engl J Med 376:584-594. https://doi.org/10.1056/NEJMsr1408795.
10. Menachery VD, Yount BL, Jr, Sims AC, Debbink K, Agnihothram SS, Gralinski LE, Graham RL, Scobey T, Plante JA, Royal SR, Swanstrom J, Sheahan TP, Pickles RJ, Corti D, Randell SH, Lanzavecchia A, Marasco WA, Baric RS. 2016. SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci U S A 113:3048-3053. https://doi.org/10.1073/pnas.1517719113.
11. Menachery VD, Yount BL, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. 2015. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med 21:1508-1513. https://doi.org/10.1038/nm.3985.
12. Agnihothram S, Yount BL, Donaldson EF, Huynh J, Menachery VD, Gralinski LE, Graham RL, Becker MM, Tomar S, Scobey TD, Osswald HL, Whitmore A, Gopal R, Ghosh AK, Mesecar A, Zambon M, Heise M, Denison MR, Baric RS. 2014. A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. mBio 5:e00047-14. https://doi.org/10.1128/mBio.00047-14.
13. Yang Y, Du L, Liu C, Wang L, Ma C, Tang J, Baric RS, Jiang S, Li F. 2014. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci U S A 111:12516-12521. https://doi.org/10.1073/pnas.1405889111.
14. Eltahla AA, Luciani F, White PA, Lloyd AR, Bull RA. 2015. Inhibitors of the hepatitis C virus polymerase; mode of action and resistance. Viruses 7:5206-5224. https://doi.org/10.3390/v7102868.
15. De Clercq E, Li G. 2016. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 29:695-747. https://doi.org/10.1128/CMR.00102-15.
16. Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J. 2006. Discovery of an RNA virus 3=¡5= exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci U S A 103:5108-5113. https://doi.org/10.1073/pnas.0508200103.
17. Eckerle LD, Lu X, Sperry SM, Choi L, Denison MR. 2007. High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J Virol 81:12135-12144. https://doi.org/10.1128/JVI.01296-07.
18. Eckerle LD, Becker MM, Halpin RA, Li K, Venter E, Lu X, Scherbakova S, Graham RL, Baric RS, Stockwell TB, Spiro DJ, Denison MR. 2010. Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog 6:e1000896-15. https://doi.org/10.1371/journal.ppat.1000896.
19. Taylor R, Kotian P, Warren T, Panchal R, Bavari S, Julander J, Dobo S, Rose A, El-Kattan Y, Taubenheim B, Babu Y, Sheridan WP. 2016. BCX4430-a broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. J Infect Publ Health 9:220-226. https://doi.org/10.1016/j.jiph.2016.04.002.
20. Chu CK, Gadthula S, Chen X, Choo H, Olgen S, Barnard DL, Sidwell RW. 2006. Antiviral activity of nucleoside analogues against SARScoronavirus (SARS-CoV). Antivir Chem Chemother 17:285-289. https:// doi.org/10.1177/095632020601700506.
21. Subissi L, Imbert I, Ferron F, Collet A, Coutard B, Decroly E, Canard B. 2014. SARS-CoV ORF1b-encoded nonstructural proteins 12-16: replicative enzymes as antiviral targets. Antiviral Res 101:122-130. https://doi.org/10.1016/j.antiviral.2013.11.006.
22. Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. 2013. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog 9:e1003565. https://doi.org/10.1371/journal.ppat.1003565.
23. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS. 2017. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 9:1-11. https://doi.org/10.1126/scitranslmed.aal3653.
24. Cho A, Saunders OL, Butler T, Zhang L, Xu J, Vela JE, Feng JY, Ray AS, Kim CU. 2012. Synthesis and antiviral activity of a series of 1=-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett 22:2705-2707. https://doi.org/10.1016/j.bmcl.2012.02.105.
25. Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, Dong L, Retterer CJ, Eaton BP, Pegoraro G, Honnold S, Bantia S, Kotian P, Chen X, Taubenheim BR, Welch LS, Minning DM, Babu YS, Sheridan WP, Bavari S. 2014. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 508:402-405. https://doi.org/10.1038/nature13027.
26. Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, Flint M, McMullan LK, Siegel D, Clarke MO, Mackman RL, Hui HC, Perron M, Ray AS, Cihlar T, Nichol ST, Spiropoulou CF. 2017. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep 7:43395. https://doi.org/10.1038/srep43395.
27. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen S-S, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S. 2016. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531:381-385. https://doi.org/10.1038/nature17180.
28. Murakami E, Niu C, Bao H, Micolochick Steuer HM, Whitaker T, Nachman T, Sofia MA, Wang P, Otto MJ, Furman PA. 2008. The mechanism of action of β-D-2=-deoxy-2=-fluoro-2=-C-methylcytidine involves a second metabolic pathway leading to β-D-2=-deoxy-2=-fluoro-2=-Cmethyluridine 5=-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 52:458-464. https://doi.org/10.1128/AAC.01184-07.
29. Sims AC, Baric RS, Yount B, Burkett SE, Collins PL, Pickles RJ. 2005. Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs. J Virol 79:15511-15524. https://doi.org/10.1128/JVI.79.24.15511-15524.2005.
30. Fehr AR, Perlman S. 2015. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282:1-23. https://doi.org/10.1007/978-1-4939-2438-7_1.
31. Daelemans D, Pauwels R, De Clercq E, Pannecouque C. 2011. A time-ofdrug addition approach to target identification of antiviral compounds. Nat Protoc 6:925-933. https://doi.org/10.1038/nprot.2011.330.
32. Sexton NR, Smith EC, Blanc H, Vignuzzi M, Peersen OB, Denison MR. 2016. Homology-based identification of a mutation in the coronavirus RNA-dependent RNA polymerase that confers resistance to multiple mutagens. J Virol 90:7415-7428. https://doi.org/10.1128/JVI.00080-16.
33. Xu X, Liu Y, Weiss S, Arnold E, Sarafianos SG, Ding J. 2003. Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design. Nucleic Acids Res 31:7117-7130. https://doi.org/10.1093/nar/gkg916.
34. Pfeiffer JK, Kirkegaard K. 2003. A single mutation in poliovirus RNAdependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc Natl Acad Sci U S A 100:7289-7294. https://doi.org/10.1073/pnas.1232294100.
35. Migliaccio G, Tomassini JE, Carroll SS, Tomei L, Altamura S, Bhat B, Bartholomew L, Bosserman MR, Ceccacci A, Colwell LF, Cortese R, De Francesco R, Eldrup AB, Getty KL, Hou XS, LaFemina RL, Ludmerer SW, MacCoss M, McMasters DR, Stahlhut MW, Olsen DB, Hazuda DJ, Flores OA. 2003. Characterization of resistance to non-obligate chainterminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem 278:49164-49170. https://doi.org/10.1074/ jbc.M305041200.
36. Coffey LL, Beeharry Y, Bordería AV, Blanc H, Vignuzzi M. 2011. Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proc Natl Acad Sci U S A 108:16038-16043. https://doi.org/10.1073/pnas.1111650108.
37. Miller V, Stürmer M, Staszewski S, Gröschel B, Hertogs K, de Béthune MP, Pauwels R, Harrigan PR, Bloor S, Kemp SD, Larder BA. 1998. The M184 V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors. AIDS 12:705-712. https://doi.org/10.1097/00002030-199807000-00006.
38. Gralinski LE, Bankhead A, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson BJM, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, Law GL, Katze MG, McWeeney S, Baric RS. 2013. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio 4:e00271-13. https://doi.org/10.1128/mBio.00271-13.
39. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JYN, Hong Z, Andino R, Cameron CE. 2000. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 6:1375-1379. https://doi.org/10.1038/ 82191.
40. Pyrc K, Bosch BJ, Berkhout B, Jebbink MF, Dijkman R, Rottier P, van der Hoek L. 2006. Inhibition of human coronavirus NL63 infection at early stages of the replication cycle. Antimicrob Agents Chemother 50:2000-2008. https://doi.org/10.1128/AAC.01598-05.
41. Sangawa H, Komeno T, Nishikawa H, Yoshida A, Takahashi K, Nomura N, Furuta Y. 2013. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob Agents Chemother 57:5202-5208. https://doi.org/10.1128/AAC.00649-13.
42. Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, Govorkova EA. 2013. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol 87:3741-3751. https://doi.org/ 10.1128/JVI.02346-12.
43. Te HS, Randall G, Jensen DM. 2007. Mechanism of action of ribavirin in the treatment of chronic hepatitis C. Gastroenterol Hepatol 3:218-225.
44. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, Simon LN. 1973. Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci U S A 70:1174-1178.
45. Derse D, Cheng Y-C, Furman PA, Clair MHS, Elion GB. 1981. Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2-hydroxyethoxymethyl)guanine triphosphate. J Biol Chem 256:11447-11451.
46. Ferrer-Orta C, Arias A, Pérez-Luque R, Escarmís C, Domingo E, Verdaguer N. 2007. Sequential structures provide insights into the fidelity of RNA replication. Proc Natl Acad Sci U S A 104:9463-9468. https://doi.org/10.1073/pnas.0700518104.
47. Wainberg MA, Drosopoulos WC, Salomon H, Hsu M, Borkow G, Parniak MA, Gu Z, Song Q, Manne J, Islam S, Castriota G, Prasad VR. 1996. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271:1282-1285. https://doi.org/10.1126/science.271.5253.1282.
48. Hsu M, Inouye P, Rezende L, Richard N, Li Z, Prasad VR, Wainberg MA. 1997. Higher fidelity of RNA-dependent DNA mispair extension by M184V drug-resistant than wild-type reverse transcriptase of human immunodeficiency virus type 1. Nucleic Acids Res 25:4532-4536. https:// doi.org/10.1093/nar/25.22.4532.
49. Subissi L, Posthuma CC, Collet A, Zevenhoven-Dobbe JC, Gorbalenya AE, Decroly E, Snijder EJ, Canard B, 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. https://doi.org/10.1073/pnas.1323705111.
50. Ferron F, Subissi L, Silveira De Morais AT, Le NTT, Sevajol M, Gluais L, Decroly E, Vonrhein C, Bricogne G, Canard B, 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. https://doi.org/10.1073/pnas.1718806115.
51. Svarovskaia ES, Gane E, Dvory-Sobol H, Martin R, Doehle B, Hedskog C, Jacobson IM, Nelson DR, Lawitz E, Brainard DM, McHutchison JG, Miller MD, Mo H. 2016. L159F and V321A sofosbuvir-associated hepatitis C virus NS5B substitutions. J Infect Dis 213:1240-1247. https://doi.org/10.1093/infdis/jiv564.
52. Pfeiffer JK, Kirkegaard K. 2005. Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice. PLoS Pathog 1:e11. https://doi.org/10.1371/journal.ppat.0010011.
53. Paredes R, Sagar M, Marconi VC, Hoh R, Martin JN, Parkin NT, Petropoulos CJ, Deeks SG, Kuritzkes DR. 2009. In vivo fitness cost of the M184V mutation in multidrug-resistant human immunodeficiency virus type 1 in the absence of lamivudine. J Virol 83:2038-2043. https://doi.org/10.1128/JVI.02154-08.
54. Yount B, Denison MR, Weiss SR, Baric RS. 2002. Systematic assembly of a full-length infectious cDNA of mouse hepatitis virus strain A59. J Virol 76:11065-11078. https://doi.org/10.1128/JVI.76.21.11065-11078.2002.
55. Sims AC, Tilton SC, Menachery VD, Gralinski LE, Schäfer A, Matzke MM, Webb-Robertson BJ, Chang J, Luna ML, Long CE, Shukla AK, Bankhead AR, Burkett SE, Zornetzer G, Tseng CT, Metz TO, Pickles R, McWeeney S, Smith RD, Katze MG, Waters KM, Baric RS. 2013. Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells. J Virol 87:3885-3902. https://doi.org/ 10.1128/JVI.02520-12.
56. Fulcher LM, Gabriel S, Burns KA, Yankaskas JR, Randell SH. 2004. Welldifferentiated human airway epithelial cell cultures. Methods Mol Med 107:183-206.
57. Scobey T, Yount BL, Sims AC, Donaldson EF, Agnihothram SS, Menachery VD, Graham RL, Swanstrom J, Bove PF, Kim JD, Grego S, Randell SH, Baric RS. 2013. Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc Natl Acad Sci U S A 110:16157-16162. https://doi.org/10.1073/pnas.1311542110.
58. Yount B, Curtis KM, Fritz EA, Hensley LE, Jahrling PB, Prentice E, Denison MR, Geisbert TW, Baric RS. 2003. Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci U S A 100:12995-13000. https://doi.org/10.1073/pnas.1735582100.