Targeting Myeloperoxidase Ameliorates Gouty Arthritis: A Virtual Screening Success Story

  • J Med Chem. 2024 Jul 25;67(14):12012-12032. doi: 10.1021/acs.jmedchem.4c00721.
Isaac de A Matos  1 ,  Jorge L Dallazen  2 ,  Lorenna R Reis  1 ,  Luiz Felipe Souza  1 ,  Regina C Bevevino  1 ,  Rafael D de Moura  1 ,  Graziella E Ronsein  1 ,  Nicolas Carlos Hoch  1 ,  Nivan Bezerra da Costa Júnior  3 ,  Soraia Kátia P Costa  2 ,  Flavia C Meotti  1
Affiliations
  • 1. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, Brazil.
  • 2. Department of Pharmacology, Institute of Biological Sciences, University of São Paulo, São Paulo 05508-000, Brazil.
  • 3. Department of Chemistry, Federal University of Sergipe, São Cristóvão 49100-000, Sergipe, Brazil.
PMID: 38991154 DOI: 10.1021/acs.jmedchem.4c00721
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-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.

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