Targeting Myeloperoxidase Ameliorates Gouty Arthritis: A Virtual Screening Success Story

This study presents a new approach for identifying myeloperoxidase
(MPO) inhibitors with strong in vivo efficacy. By combining inhibitor-like
rules and structure-based virtual screening, the pipeline achieved
a 70% success rate in discovering diverse, nanomolar-potency reversible
inhibitors and hypochlorous acid (HOCl) scavengers. Mechanistic analysis
identified RL6 as a genuine MPO inhibitor and RL7 as a potent HOCl
scavenger. Both compounds effectively suppressed HOCl production in
cells and neutrophils, with RL6 showing a superior inhibition of neutrophil
extracellular trap release (NETosis). In a gout arthritis mouse model,
intraperitoneal RL6 administration reduced edema, peroxidase activity,
and IL-1β levels. RL6 also exhibited oral bioavailability, significantly
reducing paw edema when administered orally. This study highlights
the efficacy of integrating diverse screening methods to enhance virtual
screening success, validating the anti-inflammatory potential of potent
inhibitors, and advancing the MPO inhibitor research.