Journal Article

De novo designed proteins neutralize lethal snake venom toxins

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

2025

Overview

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 more 1 , 2 . Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage 3 and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity 4 . 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 3FTxs 5 , 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. Deep learning methods have been used to design proteins that can neutralize the effects of three-finger toxins found in snake venom, which could lead to the development of safer and more accessible antivenom treatments.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 631/61/51/2314 / 64 / 64/60 / 692/308/153 / 9/74 / Acetylcholine receptors (nicotinic) / Animals / Computational neuroscience / Crystallography / Cytotoxins / Deep learning / Design / Drug Design / Effectiveness / Elapid Venoms - antagonists & inhibitors / Elapid Venoms - chemistry / Elapid Venoms - toxicity / Female / Humanities and Social Sciences / Humans / Immunization / Male / Mice / Models, Molecular / multidisciplinary / Neurotoxicity / Neurotoxins / Neurotoxins - antagonists & inhibitors / Neurotoxins - chemistry / Neurotoxins - toxicity / Polyclonal antibodies / Protein Engineering / Protein Stability / Proteins / Science / Science (multidisciplinary) / Snake bites / Snake Bites - drug therapy / Snake Venoms - antagonists & inhibitors / Snake Venoms - chemistry / Snake Venoms - toxicity / Snakes / Thermal stability / Toxins / Tropical diseases / Venom / Venom toxins