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

Autor:	Du TY; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia., Hall SR; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Chung F; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia., Kurdyukov S; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia., Crittenden E; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Patel K; School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2008, Australia., Dawson CA; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Westhorpe AP; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Bartlett KE; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Rasmussen SA; Department of Pathology and Laboratory Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, 7th Floor of MacKenzie Building, 5788 University Avenue, Halifax, NS B3H 1V8, Canada., Moreno CL; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia., Denes CE; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia., Albulescu LO; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Marriott AE; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Mackay JP; School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2008, Australia., Wilkinson MC; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Gutiérrez JM; Clodomiro Picado Institute, School of Microbiology, University of Costa Rica, P.O. Box 15501, 11501-2060 San José, Costa Rica., Casewell NR; Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK., Neely GG; Charles Perkins Centre, Dr. John and Anne Chong Lab for Functional Genomics, and School of Life and Environmental Sciences, University of Sydney, Camperdown, NSW 2006, Australia.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2024 Jul 17; Vol. 16 (756), pp. eadk4802. Date of Electronic Publication: 2024 Jul 17.
DOI:	10.1126/scitranslmed.adk4802
Abstrakt:	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.
Databáze:	MEDLINE
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