Accepted author manuscript, 1.55 MB, PDF document
Available under license: CC BY: Creative Commons Attribution 4.0 International License
Accepted author manuscript, 1.55 MB, PDF document
Available under license: CC BY: Creative Commons Attribution 4.0 International License
Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming
AU - Du, Tian Y
AU - Hall, Steven R
AU - Chung, Felicity
AU - Kurdyukov, Sergey
AU - Crittenden, Edouard
AU - Patel, Karishma
AU - Dawson, Charlotte A
AU - Westhorpe, Adam P
AU - Bartlett, Keirah E
AU - Rasmussen, Sean A
AU - Moreno, Cesar L
AU - Denes, Christopher E
AU - Albulescu, Laura-Oana
AU - Marriott, Amy E
AU - Mackay, Joel P
AU - Wilkinson, Mark C
AU - Gutiérrez, José María
AU - Casewell, Nicholas R
AU - Neely, G Gregory
PY - 2024/7/17
Y1 - 2024/7/17
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Elapid Venoms
KW - Snake Bites/drug therapy
KW - Mice
KW - Antidotes/pharmacology
U2 - 10.1126/scitranslmed.adk4802
DO - 10.1126/scitranslmed.adk4802
M3 - Journal article
C2 - 39018365
VL - 16
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 756
M1 - eadk4802
ER -