Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity.

ABSTRACT: Alphaviruses are mosquito-borne RNA viruses that pose a significant public health threat, with no FDA-approved antiviral therapeutics available. The nonstructural protein 2 helicase (nsP2hel) is an enzyme involved in unwinding dsRNA essential for alphavirus replication. This study reports the discovery and optimization of first-in-class oxaspiropiperidine inhibitors targeting nsP2hel. Structure-activity relationship (SAR) studies identified potent cyclic sulfonamide analogs with nanomolar antiviral activity against chikungunya virus (CHIKV). Biochemical analyses of nsP2hel ATPase and RNA unwindase activities showed these compounds act in a noncompetitive mode, suggesting that they are allosteric inhibitors. Viral resistance mutations mapped to nsP2hel and a fluorine-labeled analog exhibite

SUBMITTER: Muthu Ramalingam B 

PROVIDER: S-EPMC12305492 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature