TY - JOUR

T1 - De novo designed proteins neutralize lethal snake venom toxins

AU - Vázquez Torres, Susana

AU - Benard Valle, Melisa

AU - Mackessy, Stephen P.

AU - Menzies, Stefanie K.

AU - Casewell, Nicholas R.

AU - Ahmadi, Shirin

AU - Burlet, Nick J.

AU - Muratspahić, Edin

AU - Sappington, Isaac

AU - Overath, Max D.

AU - Rivera-de-Torre, Esperanza

AU - Ledergerber, Jann

AU - Laustsen, Andreas H.

AU - Boddum, Kim

AU - Bera, Asim K.

AU - Kang, Alex

AU - Brackenbrough, Evans

AU - Cardoso, Iara A.

AU - Crittenden, Edouard P.

AU - Edge, Rebecca J.

AU - Decarreau, Justin

AU - Ragotte, Robert J.

AU - Pillai, Arvind S.

AU - Abedi, Mohamad

AU - Han, Hannah L.

AU - Gerben, Stacey R.

AU - Murray, Analisa

AU - Skotheim, Rebecca

AU - Stuart, Lynda

AU - Stewart, Lance

AU - Fryer, Thomas J. A.

AU - Jenkins, Timothy P.

PY - 2025/3/6

Y1 - 2025/3/6

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-024-08393-x

DO - 10.1038/s41586-024-08393-x

M3 - Journal article

VL - 639

SP - 225

EP - 231

JO - Nature

JF - Nature

SN - 1476-4687

ER -