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Du, Tian Y., Hall, Steven, Chung, Felicity, Kurdyukov, Sergey, Crittenden, Edouard, Patel, Karishma, Dawson, Charlotte A., Westhorpe, Adam P., Bartlett, Keirah E., Rasmussen, Sean A., Moreno, Cesar L., Denes, Christopher E., Albulescu, Laura-Oana, Marriott, Amy E., Mackay, Joel P., Wilkinson, Mark C., Gutiérrez, José María, Casewell, Nicholas 
ORCID: https://orcid.org/0000-0002-8035-4719 and Neely, G. Gregory
(2024)
'Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming'. Science Translational Medicine, Vol 16, Issue 756.
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Text (This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine in Volume16, Issue 756 July 2024], DOI:10.1126/scitran)
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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.
| Item Type: | Article |
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| Subjects: | QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 630 Toxins. Antitoxins WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology |
| Digital Object Identifer (DOI): | https://doi.org/10.1126/scitranslmed.adk4802 |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 17 Sep 2024 09:18 |
| Last Modified: | 17 Sep 2024 09:20 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/25002 |
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