One-shot design of functional protein binders with BindCraft

• 成果类型: Article
• 署名作者: Pacesa, Martin; Nickel, Lennart; Schellhaas, Christian; Schmidt, Joseph; Pyatova, Ekaterina; Kissling, Lucas; Barendse, Patrick; Choudhury, Jagrity; Kapoor, Srajan; Alcaraz-Serna, Ana; Cho, Yehlin; Ghamary, Kourosh H.; Vinue, Laura; Yachnin, Brahm J.; Wollacott, Andrew M.; Buckley, Stephen; Westphal, Adrie H.; Lindhoud, Simon; Georgeon, Sandrine; Goverde, Casper A.; Hatzopoulos, Georgios N.; Gonczy, Pierre; Muller, Yannick D.; Schwank, Gerald; Swarts, Daan C.; Vecchio, Alex J.; Schneider, Bernard L.; Ovchinnikov, Sergey; Correia, Bruno E.
• 署名单位: Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss Institute of Bioinformatics; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Zurich; Wageningen University & Research; State University of New York (SUNY) System; University at Buffalo, SUNY; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; Massachusetts Institute of Technology (MIT); Swiss School of Public Health (SSPH+); Swiss Federal Institutes of Technology Domain; Swiss Institute Experimental Cancer Research; Ecole Polytechnique Federale de Lausanne
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09429-6
• 发表日期: 2025-10-09
• 关键词: allergen; gene

摘要

Protein-protein interactions are at the core of all key biological processes. However, the complexity of the structural features that determine protein-protein interactions makes their design challenging. Here we present BindCraft, an open-source and automated pipeline for de novo protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold2 (ref. 1) to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, de novo designed proteins and multi-domain nucleases, such as CRISPR-Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Last, we use cell-surface-receptor-specific binders to redirect adeno-associated virus capsids for targeted gene delivery. This work represents a significant advancement towards a 'one design-one binder' approach in computational design, with immense potential in therapeutics, diagnostics and biotechnology.