Targeting snake venom metalloproteinases: structural diversity, molecular pathogenesis and therapeutic interventions

Snake venom Metalloproteinases (SVMPs) are Zn²⁺-dependent endopeptidases categorised under metzincin superfamily and are predominantly found in venom of the "Viperidae" family snakes. They are key mediators of venom-induced pathology with associated tissue damage including haemorrhage and oedema. SVMPs are classified as P-I, P-II, and P-III depending on the domains, each differing in structural complexity and organization. Further, the conserved HEXXHXXGXXH catalytic motif organizes a Zn²⁺ ion, essential for the breakdown of peptide bonds and proteins. Given the limitations of conventional antivenom therapy, increasing attention has been directed toward targeted approaches for SVMPs neutralization, including plant-derived phytocompounds, synthetic and repurposed small-molecule inhibitors, recombinant monoclonal antibodies, and camelid-derived nanobodies. Structure-based drug discovery, molecular docking, and mechanistic studies have facilitated the identification of compounds and biologics capable of interfering with SVMP catalytic activity, substrate recognition or functionally relevant epitopes. Emerging technologies such as CRISPR-engineered venom gland organoids and artificial intelligence/machine learning-assisted molecular screening further provide opportunities for functional target validation and rational therapeutic discovery. This review integrates these conventional and emerging strategies, highlighting the structural basis of SVMPs inhibition and their potential to support the development of precise, broad-spectrum, and next-generation therapeutic interventions against SVMP-mediated envenoming.