Proteogenomics-guided functional venomics resolves the toxin arsenal and activity of Deinagkistrodon acutus venom

Abstract

Snakebite primarily impacts rural communities of Africa, Asia, and Latin America. The sharp-nosed viper ( Deinagkistrodon acutus ) is among the snakes of highest medical importance in Asia. Despite various studies on its venom using modern venomics techniques, a comprehensive understanding of composition and function of this species' venom remains lacking. We combined proteogenomics with extensive bioactivity profiling to present the first genome-level catalogue of D. acutus venom proteins and their exochemistry. Our analysis identified an unusually simple venom containing 45 components from 20 distinct protein families. Relative toxin abundances indicate that C-type lectin and C-type lectin-related protein (CTL), snake venom metalloproteinase (svMP), snake venom serine protease (svSP), and phospholipase A 2 (PLA 2 ) constitute 90 % of the venom. Bioassays targeting key aspects of viperid envenomation showed considerable concentration-dependent cytotoxicity, particularly in kidney and lung cells, and potent protease and PLA 2 activity. Factor Xa and thrombin activities were minor, and no plasmin activity was observed. Effects on haemolysis, intracellular calcium (Ca 2+ ) release, and nitric oxide (NO) synthesis were negligible. Our analysis provides the first holistic genome-based overview of the toxin arsenal of D. acutus , predicting the molecular and functional basis of its life-threatening effects, and opens novel avenues for treating envenomation by this highly dangerous snake. • First proteogenomics-based study of the venom of Deinagkistrodon acutus • Venom proteome dominated by CTL, svMP, svSP, and PLA 2 • Functional profiling shows potent protease and PLA 2 activity • Weak effect on the activation of a range of human blood coagulation factors • Remarkable cytotoxicity, particularly on kidney and lung cells

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