De novo designed proteins neutralize lethal snake venom toxins

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

Nature, 2025, vol. 639, issue 8053, 225-231

Abstract: 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 3FTxs5–7. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08393-x

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