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

Zhonglei Wang; Liyan Yang; Xian-Qing Song

doi:10.3389/fimmu.2022.1015355

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

Front Immunol. 2022 Dec 6:13:1015355. doi: 10.3389/fimmu.2022.1015355. eCollection 2022.

Authors

Zhonglei Wang^{1

2}, Liyan Yang³, Xian-Qing Song⁴

Affiliations

¹ Key Laboratory of Green Natural Products and Pharmaceutical Intermediates in Colleges and Universities of Shandong Province, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, China.
² School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
³ Shandong Provincial Key Laboratory of Laser Polarization and Information Technology, School of Physics and Physical Engineering, Qufu Normal University, Qufu, China.
⁴ General Surgery Department, Ningbo Fourth Hospital, Xiangshan, China.

Abstract

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.

Keywords: ATV006; COVID‐19; GS-621763; GS‐441524; SARS‐CoV‐2; VV116; oral version; remdesivir.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 Drug Treatment*
COVID-19*
Coronavirus RNA-Dependent RNA Polymerase* / antagonists & inhibitors
Humans
Post-Acute COVID-19 Syndrome / prevention & control
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology

Substances

GS-441524
GS-621763
Coronavirus RNA-Dependent RNA Polymerase
NSP12 protein, SARS-CoV-2