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

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. Editor's summary: Snakebite is considered a neglected tropical disease by the World Health Organization, and although antibody-based antivenoms exist, they are species specific, are expensive, and require cold storage as well as intravenous administration in a health care setting. Here, Du and colleagues conducted a whole-genome CRISPR knockout screen to identify genes required for spitting cobra venom cytotoxicity. This screen highlighted genes involved in proteoglycan biosynthesis, suggesting that heparinoids could potentially block spitting cobra venom cytotoxicity. The heparinoid tinzaparin, given subcutaneously at the time of intradermal venom injection, effectively reduced the size of the resulting dermonecrotic lesions in mice, supporting the further evaluation of this drug for the treatment of local tissue damage from spitting cobra envenoming. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

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