GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses

Michael K Lo, Robert Jordan, Aaron Arvey, Jawahar Sudhamsu, Punya Shrivastava-Ranjan, Anne L Hotard, Mike Flint, Laura K McMullan, Dustin Siegel, Michael O Clarke, Richard L Mackman, Hon C Hui, Michel Perron, Adrian S Ray, Tomas Cihlar, Stuart T Nichol, Christina F Spiropoulou, Michael K Lo, Robert Jordan, Aaron Arvey, Jawahar Sudhamsu, Punya Shrivastava-Ranjan, Anne L Hotard, Mike Flint, Laura K McMullan, Dustin Siegel, Michael O Clarke, Richard L Mackman, Hon C Hui, Michel Perron, Adrian S Ray, Tomas Cihlar, Stuart T Nichol, Christina F Spiropoulou

Abstract

GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.

Conflict of interest statement

The authors affiliated with Gilead Sciences are employees of the company and may own company stock.

Figures

Figure 1. Structural analysis of viral RdRPs…
Figure 1. Structural analysis of viral RdRPs nucleotide binding domains.
(A) Structure of nucleotide binding domain of HCV RdRP showing structural elements (motifs A and B) that interact directly with the nucleotide. (B) Structural alignment of nucleotide binding domains of viral RdRPs shows high similarity between numerous structures. (C) Structural alignment of HCV and DenV RdRP nucleotide binding domains. (D) Structural alignment of HCV and VSV RdRP nucleotide binding domains.
Figure 2. GS-5734 potently inhibits multiple virus…
Figure 2. GS-5734 potently inhibits multiple virus families.
Clustering by sequence similarity of the nucleotide-interacting regions (motifs A and B) of viral RNA-dependent RNA polymerases correlates with activity of GS-5734 (indicated by color in legend). The tree branches do not necessarily reflect evolutionary relationships (or lack thereof). For details regarding methodology, please refer to methods. †GS-5734 EC50 against MuV is higher than 100 nM, with EC50 of 0.79 μM. ‡GS-5734 is potent (EC50 < 4.5 μM) against AHFV, KFDV, TBEV, and OHFV. The parent nucleoside (Nuc) of GS-5734 is also active against DenV and HCV, but not WNV or YFV.

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