Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript’s publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

Artificial Neural Network Based Study Predicting GS-441524 As Potential Inhibitor of SARS COV-2 Activator Protein Furin: A Polypharmacology Approach

“…to target the RNA-dependent RNA polymerase (RdRp) of several viruses, including the Ebola virus, MERS-CoV, SARS-CoV, and potentially SARS-CoV-2. The latest study has further confirmed that the direct use of GS-441524 can potently inhibit the replication of SARS-CoV-2 in a mouse model [30] . In present study, another prominent antiviral molecule Grazoprevir screened out as a furin inhibitor.…”

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

“…Four nucleoside analogues that are known inhibitors of SARS-CoV-2 replication were selected as reference for studies in HAEC cultures. These included remdesivir, GS-441524 ( Li et al, 2021 ; Pruijssers et al, 2020 ; Shi et al, 2020 ; Xie et al, 2020 ; Zandi et al, 2020 ) (the parent nucleoside of remdesivir), EIDD-1931 ( Zandi et al, 2020 ; Good et al, 2021 ; Sheahan et al, 2020 ) (the parent nucleoside of molnupiravir) and AT-511 ( Good et al, 2021 ) [a guanosine nucleotide analogue with activity against hepatitis C virus (HCV)]. To select a suitable concentration range of these molecules, we first explored their effect in VeroE6 and Huh7 cell lines.…”

“…These results are in agreement with an earlier study ( Pruijssers et al, 2020 ), where the virus replication was monitored for 3 days. We demonstrated that the parent nucleoside GS-441524 ( Li et al, 2021 ; Pruijssers et al, 2020 ; Shi et al, 2020 ; Xie et al, 2020 ; Zandi et al, 2020 ) at 2 μM can also “sterilize” HAEC cultures from SARS-CoV2 as no rebound of the virus was noted several days after removal of the molecule. At 1 μM GS-441524, an intermediate antiviral potency was observed, but significant antiviral activity was not observed at 0.4 μM in the HAEC cultures.…”

Broad-Spectrum Antiviral Activity of 3D8, a Nucleic Acid-Hydrolyzing Single-Chain Variable Fragment (scFv), Targeting SARS-CoV-2 and Multiple Coronaviruses In Vitro

“…To address this issue, further studies are needed to illustrate the in vivo inhibitory effect of 3D8 scFv in hACE2-transgenic mice, hamsters, ferrets, or non-human primate models. Remdesivir conferred promising antiviral activity against SARS-CoV-2 in hACE2-transgenic mice [4,39] and rhesus macaques [40]. A combi-nation therapy of remdesivir with methylprednisolone showed beneficial effects against SARs-CoV-2 in hamsters [41].…”