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

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.

Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy

“…As such, the ester hydrolysis and the metabolism from alanine metabolite to MP-Nuc are the most essential steps for ProTide activation. However, recent findings showed that compared with remdesivir, GS-441524 had a stronger anti-SARS-CoV-2 efficacy in Vero E6 cells but a weaker efficacy in Calu-3 5 , 66 and Caco-2 cells. 5 , 66 Whether GS-441524 or isopropyl-GS-441524 can be more effective for COVID-19 treatment than remdesivir warrants further in vivo investigations.…”

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

“…In addition, it has a challenging pharmacological profile allowing intravenous administration only [39][40][41] . We demonstrate that the parent nucleoside GS-441524 [12][13][14][15][16] can "sterilize" H(s)AEC cultures from SARS-CoV2 as no rebound of the virus was noted several days after removal of the molecule. Differences in antiviral potencies of RDV and GS-441524 have been reported depending on the cell lines used, which correlates with the formation of the biologically active (5'-triphosphate) metabolite 12,13 .…”

“…We demonstrate that the parent nucleoside GS-441524 [12][13][14][15][16] can "sterilize" H(s)AEC cultures from SARS-CoV2 as no rebound of the virus was noted several days after removal of the molecule. Differences in antiviral potencies of RDV and GS-441524 have been reported depending on the cell lines used, which correlates with the formation of the biologically active (5'-triphosphate) metabolite 12,13 . Data from a pharmacokinetic study in mice suggests that GS-441524 could possibly be considered as an oral drug 12 .…”

“…Three nucleoside analogues that are known as inhibitors of SARS-CoV-2 replication were selected as reference for studies in HAEC cultures. These included GS-441524 [12][13][14][15][16] (the parent nucleoside of RDV), EIDD-1931 [16][17][18] (the active metabolite of Molnupiravir) and AT-511 17 [a guanosine nucleotide analogue with activity against hepatitis C virus (HCV)]. In order to select a suitable concentration range of these molecules to be used in the HAEC cultures, we first explored their effect in VeroE6 and Huh7 cell lines.…”

An update review of emerging small-molecule therapeutic options for COVID-19

“…In a rat pharmacokinetics study, it showed a good plasma distribution and a long half-life (t 1/2 = 4.8 h). Considering that GS-441524 is the main metabolite of remdesivir in plasma, it is speculated that GS-441524 contributes to the anti-COVID-19 effect of remdesivir [ 22 ]. GS-441524 may become a promising cheap drug candidate for the treatment of COVID-19 and future emerging CoV diseases.…”