Targeting Myeloperoxidase Ameliorates Gouty Arthritis: A Virtual Screening Success Story

Author(s):Show less -

Matos, Isaac de A. ; Dallazen, Jorge L. ; Reis, Lorenna R. ; Souza, Luiz Felipe ; Bevevino, Regina C. ; de Moura, Rafael D. ; Ronsein, Graziella E. ; Hoch, Nicolas Carlos ; da Costa Junior, Nivan Bezerra ; Costa, Soraia Katia P. ; Meotti, Flavia C.

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 67, n. 14, p. 21-pg., 2024-07-11.

Abstract

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-1 beta 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. (AU)

• FAPESP's process: 18/14898-2 - Investigations of the redox processes in inflammatory response and associated pathologies
• Grantee: Flavia Carla Meotti
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2