De novo-designed protein binders neutralize snake toxins
Research Highlight
Published: 14 February 2025
Protein engineering
Anahita Bishop1Â
Nature Biotechnology
volume 43, page 176 (2025)Cite this article
Three-finger toxins are the major component of the venom of elapid snakes and have limited immunogenicity in antivenom-producing animals, which results in a weak antibody response. Current treatments comprising polyclonal antibodies therefore often lack efficacy in preventing neurotoxicity and tissue necrosis. In a recent study published in Nature, Torres et al. use deep-learning methods to produce de novo-designed proteins to neutralize three-finger toxins.
The authors used RoseTTAFold diffusion (RFdiffusion) to design protein binders of different three-finger-toxin subclasses. These proteins prevented the binding of α-neurotoxins to nicotinic acetylcholine receptor subtypes, which would otherwise block neurotransmission and lead to paralysis. In the case of cytotoxin (a prominent functional group in the three-finger-toxin family), the protein binder was designed to directly bind the toxin, which prevented destabilization of phospholipid membranes. Using X-ray crystallography, the authors showed that the structures of the protein binders in complex with their targets match the computational designs. After in vitro validation of the top candidates, the authors challenged mice with neurotoxins and showed complete protection when preincubated with the binders as well as when the binder was administered 15 min after a lethal α-neurotoxin challenge at a 1:10 (toxin:binder) molar ratio. Mice injected with binder alone showed no negative effects at up to two weeks after injection.
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Author informationAuthors and AffiliationsNature Biotechnology https://www.nature.com/nbt/
Anahita Bishop
Corresponding authorCorrespondence to
Anahita Bishop.
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Cite this articleBishop, A. De novo-designed protein binders neutralize snake toxins.
Nat Biotechnol 43, 176 (2025). https://doi.org/10.1038/s41587-025-02575-2
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Published: 14 February 2025
Issue Date: February 2025
DOI: https://doi.org/10.1038/s41587-025-02575-2
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