Dataset Information

The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.

ABSTRACT: Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir: (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections.

Supplementary information

The online version contains supplementary material available at 10.1007/s44231-022-00021-4.

SUBMITTER: Zhu J

PROVIDER: S-EPMC9645326 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.

Zhu JiaYi J Li Yuchong Y Liang Jady J Mubareka Samira S Slutsky Arthur S AS Zhang Haibo H

Intensive care research 20221109 3-4

Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe ...[more]

PMID: 36407474

Similar Datasets

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatment strategy. Here, we evaluated the inhibitory effects of drugs on SARS-CoV-2 replication in a hamster infection model and in in vitro assays. Favipiravir significantly suppressed virus replication in hamster lungs. Remdesivir inhibited virus replication in vitro, but was not effective in the hamster model. However, GS-441524, a metabolite of remdesivir, effectively suppressed virus replication in hamsters. Co-administration of favipiravir and GS-441524 more efficiently reduced virus load in hamster lungs than did single administration of either drug for both the prophylactic and therapeutic regimens; prophylactic co-administration also efficiently inhibited lung inflammation in the infected animals. Furthermore, pretreatment of hamsters with favipiravir and GS-441524 effectively protected them from virus transmission via respiratory droplets upon exposure to infected hamsters. Repurposing and co-administration of antiviral drugs may help combat COVID-19. IMPORTANCE During a pandemic, repurposing drugs that are approved for other diseases is a quick and realistic treatment option. In this study, we found that co-administration of favipiravir and the remdesivir metabolite GS-441524 more effectively blocked SARS-CoV-2 replication in the lungs of Syrian hamsters than either favipiravir or GS-441524 alone as part of a prophylactic or therapeutic regimen. Prophylactic co-administration also reduced the severity of lung inflammation. Moreover, co-administration of these drugs to naive hamsters efficiently protected them from airborne transmission of the virus from infected animals. Since both drugs are nucleotide analogs that interfere with the RNA-dependent RNA polymerases of many RNA viruses, these findings may also help encourage co-administration of antivirals to combat future pandemics.

Dataset Information

The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.

Supplementary information

Publications

The Potential Protective Role of GS-441524, a Metabolite of the Prodrug Remdesivir, in Vaccine Breakthrough SARS-CoV-2 Infections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets