美国华盛顿大学David Baker和丹麦技术大学Timothy P. Jenkins共同合作，近期取得重要进展。他们研究提出，从头设计的蛋白质可中和致命蛇毒毒素。Baker, David课题组的一项最新研究的最新研究探明了从头设计的蛋白质可以中和致命的蛇毒毒素。2025年1月15日出版的《自然》杂志发表了这项成果。

据介绍，蛇咬伤中毒仍是一种危害严重且被忽视的热带病，每年夺走超10万条生命，还致使更多人出现严重并发症和留下长期残疾。三指毒素（3FTx）是眼镜蛇科蛇毒中的剧毒成分，可引发多种病变，包括严重的组织损伤以及对烟碱型乙酰胆碱受体的抑制，进而导致危及生命的神经毒性。目前，蛇咬伤唯一可用的治疗方法是使用从免疫动物血浆中提取的多克隆抗体，但这种抗体成本高昂，且对3FTx的疗效有限。

研究人员运用深度学习方法从头设计蛋白质，使其能够结合3FTx家族中的短链和长链 α-神经毒素以及细胞毒素。经过有限的实验筛选，研究人员获得了具有卓越热稳定性、高结合亲和力且与计算模型近乎原子层面吻合的蛋白质设计。这些设计出的蛋白质在体外能有效中和全部三个3FTx亚家族毒素，并保护小鼠免受致命神经毒素的攻击。这类高效、稳定且易于生产的毒素中和蛋白，有望为更安全、经济且广泛可及的下一代抗蛇毒血清疗法奠定基础。

除蛇咬伤治疗外，这一研究结果还凸显了计算设计如何通过大幅降低成本和资源需求，助力推动治疗药物研发的普及化，尤其是在资源有限的环境中，为被忽视热带病治疗方案的开发提供支持。

附：英文原文

Title: De novo designed proteins neutralize lethal snake venom toxins

Author: Vzquez Torres, Susana, Benard Valle, Melisa, Mackessy, Stephen P., Menzies, Stefanie K., Casewell, Nicholas R., Ahmadi, Shirin, Burlet, Nick J., Muratspahi, Edin, Sappington, Isaac, Overath, Max D., Rivera-de-Torre, Esperanza, Ledergerber, Jann, Laustsen, Andreas H., Boddum, Kim, Bera, Asim K., Kang, Alex, Brackenbrough, Evans, Cardoso, Iara A., Crittenden, Edouard P., Edge, Rebecca J., Decarreau, Justin, Ragotte, Robert J., Pillai, Arvind S., Abedi, Mohamad, Han, Hannah L., Gerben, Stacey R., Murray, Analisa, Skotheim, Rebecca, Stuart, Lynda, Stewart, Lance, Fryer, Thomas J. A., Jenkins, Timothy P., Baker, David

Issue&Volume: 2025-01-15

Abstract: Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more1,2. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage3 and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity4. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs5,6,7. Here we used deep learning methods to de novo design proteins to bind short-chain and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, we obtained protein designs with remarkable thermal stability, high binding affinity and near-atomic-level agreement with the computational models. The designed proteins effectively neutralized all three 3FTx subfamilies in vitro and protected mice from a lethal neurotoxin challenge. Such potent, stable and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective and widely accessible next-generation antivenom therapeutics. Beyond snakebite, our results highlight how computational design could help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for the development of therapies for neglected tropical diseases.

DOI: 10.1038/s41586-024-08393-x

Source: https://www.nature.com/articles/s41586-024-08393-x