Mechanism of Inhibition of the Active Triphosphate Form of 2′-α-Fluoro,2′-β-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Yellow fever virus (YFV) is a deadly mosquito-borne flavivirus that infects approximately 200,000 individuals each year. YFV outbreak and infection are persistent throughout South America Africa, demonstrating significant epidemic potential. Although an approved effective vaccine exists, the zoonotic nature of undermines any potential eradication efforts, highlighting need for effective, direct-acting antivirals. Essential viral replication, RNA-dependent RNA polymerase (RdRp) proven therapeutic target. A prominent example includes sofosbuvir, 2'-α-fluoro,2'-β-methyluridine prodrug treatment hepatitis C (HCV), has demonstrated efficacy against in vitro. structurally similar 2'-α-fluoro, 2'-β-bromouridine exhibited potent anti-YFV activity both vitro vivo. Here, we expressed full-length nonstructural protein 5 from insect cells to investigate active triphosphate form these prodrugs. Enzyme kinetics indicate nucleotide analogs incorporated less efficiently than UTP. Once incorporated, inhibit synthesis through immediate chain termination. Omitting 2'-β-modification alleviates inhibition synthesis, its role eliciting antiviral effect. S282T well-characterized mutation motif B HCV RdRp confers resistance sofosbuvir. We discovered analogous substitution (S603T) improved discrimination 2'-α-fluoro,2'-β-modified uridine analogs. Collectively, our findings explain their observed identify conserved mechanism resistance. Based on vivo action, 2'-fluoro,2'-bromouridine shows future strategies YFV.

Language: Английский

Discovery of GS-7682, a Novel 4′-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(15), P. 12945 - 12968

Published: July 17, 2024

Acute respiratory viral infections, such as pneumovirus and picornavirus exacerbate disease in COPD asthma patients. A research program targeting syncytial virus (RSV) led to the discovery of GS-7682 (

Language: Английский