Molecular dissection of cobra venom highlights heparinoids as an effective snakebite antidote

Snakebite affects ~1.8 million people annually. The current standard of care are antibody-based antivenoms, which are difficult to access and are not effective against local tissue injury, the primary cause of morbidity. Here we use a functional genomics approach to define human genes that genetically interact with spitting cobra venoms. Most genes that confer resistance to venom cytotoxicity control proteoglycan biosynthesis, suggesting heparinoids as possible inhibitors. Here we show that heparinoids prevent venom cytotoxicity by inhibiting three-finger cytotoxins. Critically, the FDA-approved heparinoid tinzaparin was found to reduce tissue damage in vivo when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom mechanisms provides new insight into how we can treat cobra bites, information that can help improve the lives of millions of people worldwide. Whole genome pooled KO CRISPR screen using Toronto KnockOut Library v3 (TKOv3) on HAPI cells treated with venom from Naja pallida and Naja nigricollis cobra venoms. Cells from treated and control were taken for Next Generation Sequencing (NGS).