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.
Centre for Snakebite Research and Interventions, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK.
Sci Transl Med. 2024 Jul 17;16(756):eadk4802. doi: 10.1126/scitranslmed.adk4802.
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 , , , , , , and , 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.
每年约有 180 万人遭受蛇咬伤。目前的治疗标准包括基于抗体的抗蛇毒血清，但这些抗蛇毒血清难以获得，而且通常对局部组织损伤（发病率的主要原因）无效。在这里，我们使用了一个汇集的全基因组 CRISPR 敲除筛选来定义人类基因，当这些基因被靶向时，它们可以改变细胞对喷毒眼镜蛇毒液的反应。研究发现，有很大一部分修饰基因控制着蛋白聚糖的生物合成，从而赋予了对毒液细胞毒性的抗性，其中包括 、 、 、 、 、 和 ，我们独立验证了这些基因。这一发现表明肝素类物质可能是潜在的抑制剂。肝素类物质通过与三指细胞毒素结合来预防毒液的细胞毒性，而美国食品和药物管理局批准的肝素类药物亭扎肝素以一种具有医学相关性的途径和剂量给药时，被发现可以减少小鼠的组织损伤。总的来说，我们对眼镜蛇毒液细胞毒性的系统分子剖析为我们如何更好地治疗眼镜蛇蛇咬伤提供了思路。
