Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Nature

Volumn 531, Issue 7594, 2016, Pages 381-385

  Warren, Travis K ^a   Jordan, Robert ^b   Lo, Michael K ^c   Ray, Adrian S ^b   Mackman, Richard L ^b   Soloveva, Veronica ^a   Siegel, Dustin ^b   Perron, Michel ^b   Bannister, Roy ^b   Hui, Hon C ^b   Larson, Nate ^b   Strickley, Robert ^b   Wells, Jay ^a   Stuthman, Kelly S ^a   Van Tongeren, Sean A ^a   Garza, Nicole L ^a   Donnelly, Ginger ^a   Shurtleff, Amy C ^a   Retterer, Cary J ^a   Gharaibeh, Dima ^a   Zamani, Rouzbeh ^a   Kenny, Tara ^a   Eaton, Brett P ^a   Grimes, Elizabeth ^a   Welch, Lisa S ^a,e   Gomba, Laura ^a   Wilhelmsen, Catherine L ^a   Nichols, Donald K ^a   Nuss, Jonathan E ^a   Nagle, Elyse R ^a   Kugelman, Jeffrey R ^a   Palacios, Gustavo ^a   Doerffler, Edward ^b   Neville, Sean ^b   Carra, Ernest ^b   Clarke, Michael O ^b   Zhang, Lijun ^b   Lew, Willard ^b   Ross, Bruce ^b   Wang, Queenie ^b   Chun, Kwon ^b   Wolfe, Lydia ^b   Babusis, Darius ^b   Park, Yeojin ^b   Stray, Kirsten M ^b   Trancheva, Iva ^b   Feng, Joy Y ^b   Barauskas, Ona ^b   Xu, Yili ^b   Wong, Pamela ^b   Braun, Molly R ^d   Flint, Mike ^c   McMullan, Laura K ^c   Chen, Shan Shan ^b   Fearns, Rachel ^d   Swaminathan, Swami ^b   Mayers, Douglas L ^a,f   Spiropoulou, Christina F ^c   Lee, William A ^b   Nichol, Stuart T ^c   Cihlar, Tomas ^b   Bavari, Sina ^a   more..

^a UNITED STATES ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES   (United States)

^b GILEAD SCIENCES   (United States)

^c CENTERS FOR DISEASE CONTROL AND PREVENTION   (United States)

^d BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e LOKET Consulting   (United States)

^f LOKET Consulting ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DERIVATIVE; ANTIVIRUS AGENT; GS 5734; PRODRUG; UNCLASSIFIED DRUG; ALANINE; GS-5734; RIBONUCLEOTIDE;

BLOOD; CELLS AND CELL COMPONENTS; DRUG; MOLECULAR ANALYSIS; PATHOGENICITY; PHYSIOLOGY; PRIMATE; RNA; VIRAL DISEASE; VIRUS;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ARTICLE; BRAIN; CELL ASSAY; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; EBOLA HEMORRHAGIC FEVER; EBOLAVIRUS; EC50; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; LOADING DRUG DOSE; MALE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PLASMA HALF LIFE; POST EXPOSURE PROPHYLAXIS; PRIORITY JOURNAL; RHESUS MONKEY; SINGLE DRUG DOSE; TESTIS; TREATMENT DURATION; VIRUS INHIBITION; VIRUS REPLICATION; AMINO ACID SEQUENCE; ANALOGS AND DERIVATIVES; ANIMAL; ANTIBODY SPECIFICITY; DRUG EFFECTS; HELA CELL LINE; HEMORRHAGIC FEVER, EBOLA; MOLECULAR GENETICS; TUMOR CELL LINE; VIROLOGY;

WEST AFRICA;

ANIMALIA; EBOLA VIRUS; MACACA MULATTA; PRIMATES; RESPIRATORY SYNCYTIAL VIRUS; RNA VIRUSES;

ALANINE; AMINO ACID SEQUENCE; ANIMALS; ANTIVIRAL AGENTS; CELL LINE, TUMOR; EBOLAVIRUS; FEMALE; HELA CELLS; HEMORRHAGIC FEVER, EBOLA; HUMANS; MACACA MULATTA; MALE; MOLECULAR SEQUENCE DATA; ORGAN SPECIFICITY; PRODRUGS; RIBONUCLEOTIDES;

EID: 84982234143     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature17180     Document Type: Article

References (37)

1. World Health Organization. Ebola Situation Report-3 February 2016. http://apps.who.int/ebola/current-situation/ebola-situation-report-3-february-2016 (2016
2. Nanyonga, M., Saidu, J., Ramsay, A., Shindo, N., & Bausch, D. G. Sequelae of Ebola virus disease, Kenema District, Sierra Leone. Clin. Infect. Dis. 62, 125-126 (2016
3. Varkey J. B., et al. Persistence of Ebola virus in ocular fluid during convalescence. N. Engl. J. Med. 372, 2423-2427 (2015
4. Mate S. E., et al. Molecular evidence of sexual transmission of Ebola virus. N. Engl. J. Med. 373, 2448-2454 (2015
5. Deen G. F., et al. Ebola RNA persistence in semen of Ebola virus disease survivors-preliminary report. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1511410 (2015
6. Kuhn, J. H. Filoviruses: A Compendium of 40 Years of Epidemiological, Clinical, and Laboratory Studies (SpringWien, 2008
7. Kupferschmidt, K., & Cohen, J. Infectious diseases. Ebola drug trials lurch ahead. Science 347, 701-702 (2015
8. Smither S. J., et al. Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in A mouse model. Antiviral Res. 104, 153-155 (2014
9. Oestereich L., et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in A small animal model. Antiviral Res. 105, 17-21 (2014
10. McMullan L. K., et al. The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus. Antiviral Res. 125, 71-78 (2016
11. Sissoko D., et al. Favipiravir in patients with Ebola virus disease: early results of the JIKI trial in Guinea. Conference of Retroviruses and Opportunistic Infections abstr. 103-ALB (Seattle, 2015
12. Chimerix. Brincidofovir Will Not Be Considered in Further Clinical Trials in Ebola Virus Disease. http://ir.chimerix.com/releasedetail.cfm?ReleaseID=893927 (2015
13. Warren T. K., et al. Protection against filovirus diseases by A novel broadspectrum nucleoside analogue BCX4430. Nature 508, 402-405 (2014
14. BioCryst Pharmaceuticals. BioCryst Announces Study Results for BCX4430 in A Non-Human Primate Model of Ebola Virus Infection. http://investor.shareholder. com/biocryst/releasedetail.cfm?ReleaseID=888802 (2014
15. Thi E. P. et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makonainfected nonhuman primates. Nature 521, 362-365 (2015
16. Qiu X., et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514, 47-53 (2014
17. Olinger G. G. Jr, et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc. Natl Acad. Sci. USA 109, 18030-18035 (2012
18. Tekmira Pharmaceuticals Corporation. Tekmira Provides Update on TKM-Ebola-Guinea. http://www.sec.gov/Archives/edgar/data/1447028/000117184315003522/newsrelease.htm (2015
19. Cho A., et al. Synthesis and antiviral activity of A series of 1'-substituted 4-Aza-7, 9-dideazaadenosine C-nucleosides. Bioorg. Med. Chem. Lett. 22, 2705-2707 (2012
20. Murakami, E., et al. The mechanism of action of β-d-2'-deoxy-2'-fluoro-2'-Cmethylcytidine involves A second metabolic pathway leading to β-d-2'-deoxy-2'-fluoro-2'-C-methyluridine 5?-Triphosphate, A potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother. 52, 458-464 (2008
21. Mackman R. L., Parrish, J. P., Ray, A. S., & Theodore, D. A. Methods and compounds for treating respiratory syncytial virus infections. US Patent 2011045102 2011
22. Jácome, R., Becerra, A., Ponce de Leon, S., & Lazcano, A. Structural analysis of monomeric RNA-dependent polymerases: Evolutionary and therapeutic implications. PLoS ONE 10, e0139001 (2015
23. Bahar, F. G., Ohura, K., Ogihara, T., & Imai, T. Species difference of esterase expression and hydrolase activity in plasma. J. Pharm. Sci. 101, 3979-3988 (2012
24. Hunt, L., et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect. Dis. 15, 1292-1299 (2015
25. Martins K., et al. Characterization of clinical and immunological parameters during Ebola virus infection of rhesus macaques. Viral Immunol. 28, 32-41 (2015
26. Uebelhoer, L. S., et al. High-Throughput, luciferase-based reverse genetics systems for identifying inhibitors of Marburg and Ebola viruses. Antiviral Res. 106, 86-94 (2014
27. Towner J. S., et al. Generation of eGFP expressing recombinant Zaire Ebolavirus for analysis of early pathogenesis events and high-Throughput antiviral drug screening. Virology 332, 20-27 (2005
28. Shao, R., & Guo, X. Human microvascular endothelial cells immortalized with human telomerase catalytic protein: A model for the study of in vitro angiogenesis. Biochem. Biophys. Res. Commun. 321, 788-794 (2004
29. Mason S. W., et al. Polyadenylation-dependent screening assay for respiratory syncytial virus RNA transcriptase activity and identification of an inhibitor. Nucleic Acids Res. 32, 4758-4767 (2004
30. Durand-Gasselin L., et al. Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys. Mol. Pharm. 6, 1145-1151 (2009
31. Noton, S. L., Deflube, L. R., Tremaglio, C. Z., & Fearns, R. The respiratory syncytial virus polymerase has multiple RNA synthesis activities at the promoter. PLoS Pathog. 8, e1002980 (2012
32. Noton S. L., et al. Respiratory syncytial virus inhibitor AZ-27 differentially inhibits different polymerase activities at the promoter. J. Virol. 89, 7786-7798 (2015
33. Tremaglio, C. Z., Noton, S. L., Deflube, L. R., & Fearns, R. Respiratory syncytial virus polymerase can initiate transcription from position 3 of the leader promoter. J. Virol. 87, 3196-3207 (2013
34. Lodeiro M. F., et al. Identification of multiple rate-limiting steps during the human mitochondrial transcription cycle in vitro. J. Biol. Chem. 285, 16387-16402 (2010
35. Warren T. K., et al. Euthanasia assessment in Ebola virus infected nonhuman primates. Viruses 6, 4666-4682 (2014
36. Kugelman J. R., et al. Emergence of Ebola Virus escape variants in infected nonhuman primates treated with the MB-003 antibody cocktail. Cell Rep. 12, 2111-2120 (2015
37. Kugelman J. R., et al. Ebola virus genome plasticity as A marker of its passaging history: A comparison of in vitro passaging to non-human primate infection. PLoS ONE 7, e50316 (2012).