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.
Highlights
Viruses belonging to the families Paramyxoviridae, Coronaviridae and Filoviridae include zoonotic and human pathogens that are of significant public health concern, ranging from vaccine-preventable diseases such as Measles (MV) and Mumps (MuV) viruses to highly pathogenic viruses such as Nipah (NiV), Middle East Respiratory Syndrome (MERS) and Ebola (EBOV) viruses, for which there are currently no approved therapeutics for human use
We confirmed the activity of nucleoside analog GS-441524 (Nuc) against wild-type EBOV (Makona strain), NiV (Malaysian and Bangladesh genotypes) and Hendra virus (HeV) using assays which measured inhibition of virus antigen expression, virus-induced cytopathic effect (CPE), and virus titer (Supplementary Figures 2–4, Supplementary Table 1)
Arenaviridae (Lassa virus (LASV)), Rhabdoviridae (Vesicular Stomatitis virus (VSV)), Bunyaviridae (Rift Valley Fever virus (RVFV)15, Crimean Congo Hemorrhagic Fever virus (CCHFV)16), and several tick-borne members of Flaviviridae (Alkhurma Hemorrhagic Fever virus (AHFV), Kyasanur Forest Disease virus (KFDV), Omsk Hemorrhagic Fever virus (OHFV), Tick-borne encephalitis (TBEV)), we observed little to no antiviral activity (Table 1; Supplementary Figures 1–3; Supplementary Table 1)
Summary
Nuc EC50/EC90 (μM)/[SI] 1.6/6.7/[31] 3.1/11/[16] 1.3/3.3/[38] 1.0/2.5/[50]# NT 1.9/4.6/[26] 1.5/5.7/[33] 2.2/4.0 [22]. GS-5734 is a prodrug that is designed to deliver the nucleoside monophosphate into the cell, thereby circumventing the rate-limiting first phosphorylation step and allowing for efficient formation of the active triphosphate species Consistent with this notion, GS-5734 exhibited 10 to 100-fold higher antiviral potency relative to Nuc when tested against reporter and wild-type filo-, pneumo-, and paramyxoviruses, yielding EC50 values ranging from 0.003 to 0.79 μM (Table 1, Supplementary Table 2; Supplementary Figures 6–8). As was done for Nuc, we evaluated the activity of GS-5734 across other virus families and observed significantly lower activity, with micromolar EC50 values against tick-borne flaviviruses and LASV, and minimal to no antiviral activity against bunyaviruses (Table 1; Supplementary Table 2; Supplementary Figures 6–8). Depending on further careful assessment of its safety and efficacy profile, GS-5734 could be considered for the treatment of prevalent respiratory infections (RSV, hPIV3, hMPV), as well as for controlling recurring outbreaks of MV globally among under-vaccinated populations
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