De novo designed proteins neutralize lethal snake venom toxins

• 成果类型: Article
• 署名作者: Vazquez Torres, Susana; Benard Valle, Melisa; Mackessy, Stephen P.; Menzies, Stefanie K.; Casewell, Nicholas R.; Ahmadi, Shirin; Burlet, Nick J.; Muratspahic, 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
• 署名单位: University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Technical University of Denmark; University of Northern Colorado; University of Liverpool; Liverpool School of Tropical Medicine; Liverpool School of Tropical Medicine; University of Liverpool; Lancaster University; University of Liverpool; Massachusetts Institute of Technology (MIT); University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2024
• DOI: 10.1038/s41586-024-08393-x
• 发表日期: 2025-03-06
• 关键词: naja-kaouthia; antivenoms; toxicity

摘要

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 alpha-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.