Purified zymogens reveal mechanisms of snake venom metalloproteinase auto-activation
Year: 2026
Type: article
Abstract: ABSTRACT Snake venoms contain diverse mixtures of toxins that evolved to incapacitate prey, but in humans they cause extensive pathology following snakebite envenomation. In viper venom, some of the most potent toxins are the haemorrhagic and coagulopathic snake venom metalloproteinases (SVMPs). Because venoms contain a SVMP cocktail, and due to their cytotoxicity, SVMP characterizations have been hampered by the lack of purified enzymes. By incorporating their prodomain, which blocks the active SVMP site, we overcame their cytotoxicity and enabled recombinant production of zymogens from all three structurally variable SVMP classes (PI, PII and PIII) using our baculovirus/insect cell expression system. Zymogens were auto-activated by incubation with Zn 2+ ions, resulting in prodomain cleavage, PII disintegrin cleavage and PIII prodomain proteolysis. Auto-activated SVMPs were characterized using protein substrate degradation, platelet aggregation and blood coagulation assays, benchmarked to native venom-purified SVMP. Our recombinant zymogen production protocol is generically applicable for the expression of SVMPs, unlocking biomedical use in haematology, and discovery of novel snakebite therapeutics.
Source: eLife
Authors: Sophie Hall, Iara Aimê Cardoso, Mark C. Wilkinson, Maria Molina Carretero, Srikanth Lingappa, Bronwyn Rand, Dakang Shen, Johara Boldrini-França, Richard Stenner, Stefanie K. Menzies, Georgia Balchin, Konrad Kamil Hus, Renaud Vincentelli, Andrew Mumford, Alastair W. Poole, Nicholas R. Casewell, Imre Berger, Christiane Schaffitzel
Institutions: University of Bristol, Liverpool School of Tropical Medicine, Lancaster University, Rzeszów University of Technology, Centre National de la Recherche Scientifique, Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques, Max Planck-Bristol Centre for Minimal Biology
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Haemotoxic and cytotoxic snake venom metalloproteinases - production, enzymatic specificity, snakebite treatment, and biomedical use, Novel platforms to develop polyspecifically-effective, safe, affordable and thermostable monoclonal camelid VHH nanobodies to treat snake venom-induced necrosis in India and sub-Saharan Africa, Advancing Antivenom Therapy with ADDovenom: Targeting Neurotoxins in Mamba Snake Envenoming Using ADDobodies and ADDomers, ADDovenom: Novel Snakebite Therapy Platform of Unparalleled Efficacy, Safety and Affordability, G6228280817, G7267061510, G8368963011
OpenAlex ID: W7164214462