Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition.

Wei Ye,Yuewu Yang,Hui Zhang,Zhikai Xu,Yangchao Dong,Chuantao Ye,Hongwei Ma,Linfeng Cheng,Dan Wang,Min Yao,He Liu,Fanglin Zhang,Liang Zhang,Yuan Wang,Yingfeng Lei,Xin Lv,Libin Qi

doi:10.3389/fmicb.2020.01105

Wei Ye, Yuewu Yang + Show 15 more

Open Access

https://doi.org/10.3389/fmicb.2020.01105

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Abstract

Human enteroviruses are responsible for diverse diseases, from mild respiratory symptoms to fatal neurological complications. Currently, no registered antivirals have been approved for clinical therapy. Thus, a therapeutic agent for the enterovirus-related disease is urgently needed. Remdesivir (GS-5734) is a novel monophosphoramidate adenosine analog prodrug that exhibits potent antiviral activity against diverse RNA virus families, including positive-sense Coronaviridae and Flaviviridae and negative-sense Filoviridae, Paramyxoviridae, and Pneumoviridae. Currently, remdesivir is under phase 3 clinical development for disease COVID-19 treatment. Here, we found that remdesivir impeded both EV71 viral RNA (vRNA) and complementary (cRNA) synthesis, indicating that EV71 replication is inhibited by the triphosphate (TP) form of remdesivir. Moreover, remdesivir showed potent antiviral activity against diverse enteroviruses. These data extend the remdesivir antiviral activity to enteroviruses and indicate that remdesivir is a promising antiviral treatment for EV71 and other enterovirus infections.

Highlights

IntroductionFamily Picornaviridae, genus enterovirus, are non-enveloped, single-stranded RNA viruses
Human enteroviruses, family Picornaviridae, genus enterovirus, are non-enveloped, single-stranded RNA viruses
Remdesivir showed a dose-dependent inhibition of enterovirus 71 (EV71) replication (Figure 1A, EC50 = 0.991 μM) and had little effect on cell viability (Figure 1B), EV71 replication seemed slightly enhanced at low remdesivir concentrations (0.01 ∼ 0.1 μM)

Summary

Introduction

Family Picornaviridae, genus enterovirus, are non-enveloped, single-stranded RNA viruses. Enteroviruses include a large number of viruses and are characterized into four species (A∼D) responsible for diverse diseases, including poliovirus (PV), which causes poliomyelitis; some coxsackieviruses (CVs), and echovirus, which cause myocarditis; and enterovirus 70 (EV70), which causes enteroviral conjunctivitis. The most prevalent enteroviruses, causing hand, foot and mouth disease (HFMD), are endemic worldwide, and the top two pathogens are coxsackie A16 virus (CAV16), and enterovirus 71 (EV71). EV71 was first identified in 1969 in California, United States (Schmidt et al, 1974) and is a reemerging pathogen worldwide responsible for HFMD and other fatal neurological diseases, including meningitis, neurogenic pulmonary edema, acute paralysis, and reduced cognitive function. Since a massive outbreak in 2008, HFMD has become widespread in China, with over 2,000,000 cases annually.

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