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Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered ver...

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Autores principales: Wang, Zhonglei, Yang, Liyan, Song, Xian-qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763260/
https://www.ncbi.nlm.nih.gov/pubmed/36561747
http://dx.doi.org/10.3389/fimmu.2022.1015355
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author Wang, Zhonglei
Yang, Liyan
Song, Xian-qing
author_facet Wang, Zhonglei
Yang, Liyan
Song, Xian-qing
author_sort Wang, Zhonglei
collection PubMed
description GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.
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spelling pubmed-97632602022-12-21 Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase Wang, Zhonglei Yang, Liyan Song, Xian-qing Front Immunol Immunology GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524. Frontiers Media S.A. 2022-12-06 /pmc/articles/PMC9763260/ /pubmed/36561747 http://dx.doi.org/10.3389/fimmu.2022.1015355 Text en Copyright © 2022 Wang, Yang and Song https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wang, Zhonglei
Yang, Liyan
Song, Xian-qing
Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title_full Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title_fullStr Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title_full_unstemmed Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title_short Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase
title_sort oral gs-441524 derivatives: next-generation inhibitors of sars‐cov‐2 rna‐dependent rna polymerase
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763260/
https://www.ncbi.nlm.nih.gov/pubmed/36561747
http://dx.doi.org/10.3389/fimmu.2022.1015355
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AT songxianqing oralgs441524derivativesnextgenerationinhibitorsofsarscov2rnadependentrnapolymerase