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

被引：1125

作者：

Warren, Travis K. ^{[1
,2
]}

Jordan, Robert ^{[3
]}

Lo, Michael K. ^{[4
]}

Ray, Adrian S. ^{[3
]}

Mackman, Richard L. ^{[3
]}

Soloveva, Veronica ^{[1
,2
]}

Siegel, Dustin ^{[3
]}

Perron, Michel ^{[3
]}

Bannister, Roy ^{[3
]}

Hui, Hon C. ^{[3
]}

Larson, Nate ^{[3
]}

Strickley, Robert ^{[3
]}

Wells, Jay ^{[1
]}

Stuthman, Kelly S. ^{[1
]}

Van Tongeren, Sean A. ^{[1
]}

Garza, Nicole L. ^{[1
]}

Donnelly, Ginger ^{[1
]}

Shurtleff, Amy C. ^{[1
]}

Retterer, Cary J. ^{[1
]}

Gharaibeh, Dima ^{[1
]}

Zamani, Rouzbeh ^{[1
]}

Kenny, Tara ^{[1
]}

Eaton, Brett P. ^{[1
]}

Grimes, Elizabeth ^{[1
]}

Welch, Lisa S. ^{[1
,6
]}

Gomba, Laura ^{[1
,2
]}

Wilhelmsen, Catherine L. ^{[1
]}

Nichols, Donald K. ^{[1
]}

Nuss, Jonathan E. ^{[1
,2
]}

Nagle, Elyse R. ^{[1
]}

Kugelman, Jeffrey R. ^{[1
]}

Palacios, Gustavo ^{[1
]}

Doerffler, Edward ^{[3
]}

Neville, Sean ^{[3
]}

Carra, Ernest ^{[3
]}

Clarke, Michael O. ^{[3
]}

Zhang, Lijun ^{[3
]}

Lew, Willard ^{[3
]}

Ross, Bruce ^{[3
]}

Wang, Queenie ^{[3
]}

Chun, Kwon ^{[3
]}

Wolfe, Lydia ^{[3
]}

Babusis, Darius ^{[3
]}

Park, Yeojin ^{[3
]}

Stray, Kirsten M. ^{[3
]}

Trancheva, Iva ^{[3
]}

Feng, Joy Y. ^{[3
]}

Barauskas, Ona ^{[3
]}

Xu, Yili ^{[3
]}

Wong, Pamela ^{[3
]}

机构：

[1] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA

[2] US Army, Med Res Inst Infect Dis, Therapeut Dev Ctr, Ft Detrick, MD 21702 USA

[3] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA

[4] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA

[5] Boston Univ, Sch Med, Boston, MA 02118 USA

[6] LOKET Consulting, Clarksburg, MD 20871 USA

[7] Cocrystal Pharma, Tucker, GA 30084 USA

来源：

NATURE | 2016年 / 531卷 / 7594期

关键词：

INFECTED NONHUMAN-PRIMATES; ANTIVIRAL ACTIVITY; T-705; FAVIPIRAVIR; HIGH-THROUGHPUT; POLYMERASE; INHIBITOR; MODEL; PROTECTION; MACAQUES; PROMOTER;

D O I：

10.1038/nature17180

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae(1). No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

引用

页码：381 / +

页数：19

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