Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity.

ABSTRACT: Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine 1, a first-in-class inhibitor of the CHIKV nsP2 RNA helicase (nsP2hel), into its constitutive enantiomers and characterization of their antiviral activity. The enantiomer (R)-1 exhibited potent inhibition of viral replication, nsP2hel ATPase activity, and dsRNA unwinding, while the (S)-1 enantiomer was >100-fold less active. The (R)-1 enantiomer also demonstrated a high selectivity for CHIKV over other RNA viruses and for nsP2hel over other RNA helicases. Direct binding of (R)-1 to the nsP2hel protein was confirmed by ¹⁹F NM

SUBMITTER: Muthu Ramalingam B 

PROVIDER: S-EPMC12340965 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature