Structural and mechanistic insights for calpain drug development

INTRODUCTION: -activated cysteine proteases with broad roles in cell signaling, cytoskeletal remodeling, cell survival, differentiation, and tissue homeostasis. Calpain activity is implicated in multiple facets of human physiology, and its dysregulation has been reported in numerous pathologies. Yet, therapeutic targeting of calpains has been limited by challenges in achieving calpain-specific inhibition, owing to their complex biology and substrate diversity. AREAS COVERED: This review covers structural-, molecular- and cell-biology, disease associations, and recent intellectual property activity relevant to calpain drug development. Structural aspects include the domain architecture of classical and non-classical calpains, ancillary domains, calpastatin-mediated inhibition, homo- and heterodimerization, and emerging structural models. Calpains are considered in the broader landscape of cysteine proteases to highlight likely off-target liabilities. Disease- and pathology-focused sections discuss calpain-mediated signaling in neurodegeneration, muscular dystrophy, ocular disease, diabetes, endometriosis, cardiovascular pathology, fibrosis, and cancer. Strategies for calpain modulation are overviewed, including active-site, calpastatin-mimetic, and allosteric inhibitors, gene therapy, and RNA-based approaches. EXPERT OPINION: A shift beyond pan-calpain inhibition toward isoform-selective drug discovery, improved biomarkers, and accumulating structural insights offers new opportunities. Developing calpain-specific and isoform-selective therapeutics remains an exciting unmet opportunity in cancer, neurodegeneration, retinopathy, muscular dystrophy, and other diseases.