Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming

Du, Tian Y and Hall, Steven R and Chung, Felicity and Kurdyukov, Sergey and Crittenden, Edouard and Patel, Karishma and Dawson, Charlotte A and Westhorpe, Adam P and Bartlett, Keirah E and Rasmussen, Sean A and Moreno, Cesar L and Denes, Christopher E and Albulescu, Laura-Oana and Marriott, Amy E and Mackay, Joel P and Wilkinson, Mark C and Gutiérrez, José María and Casewell, Nicholas R and Neely, G Gregory (2024) Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming. Science Translational Medicine, 16 (756): eadk4802. ISSN 1946-6234

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Abstract

Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause of morbidity. Here, we used a pooled whole-genome CRISPR knockout screen to define human genes that, when targeted, modify cell responses to spitting cobra venoms. A large portion of modifying genes that conferred resistance to venom cytotoxicity was found to control proteoglycan biosynthesis, including EXT1, B4GALT7, EXT2, EXTL3, XYLT2, NDST1, and SLC35B2, which we validated independently. This finding suggested heparinoids as possible inhibitors. Heparinoids prevented venom cytotoxicity through binding to three-finger cytotoxins, and the US Food and Drug Administration-approved heparinoid tinzaparin was found to reduce tissue damage in mice when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom cytotoxicity provides insight into how we can better treat cobra snakebite envenoming.