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.

The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy in vitro to provide some essential guidance for anti-SARS-CoV-2 drug research and development.