Species Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with <i>in Vivo</i> Anti-alphaviral Activity.

ABSTRACT: RA-0002034 (1) is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower clearance observed in human hepatocytes and preclinical species such as rats, dogs, and monkeys. Cross-species studies confirmed the dominance of GST-driven metabolism in mice, whereas oxidative pathways were more pronounced in dogs. Despite rapid systemic clearance, 1 achieved antiviral efficacy in mice, reducing CHIKV viral loads in multiple tissues. Initial estimatio

SUBMITTER: Hossain MA 

PROVIDER: S-EPMC11761022 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature