articleNature Chemical BiologyJun 20, 2025HYBRID OA

Accurate de novo design of high-affinity protein-binding macrocycles using deep learning

SRStephen RettieDJDavid JuergensVAVictor AdebomiYFYensi Flores BuesoQZQinqin Zhao

University of Washington · University College Cork · +7 more institutions

PubMed
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Abstract

Abstract Developing macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource intensive and provide little control over binding mode. Despite progress in protein design, there are currently no robust approaches for de novo design of protein-binding macrocycles. Here we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic binders against protein targets of interest. We tested 20 or fewer designed macrocycles against each of four diverse proteins and obtained binders with medium to high affinity against all targets. For one of the targets, Rhombotarget A (RbtA), we designed a high-affinity binder ( K d < 10 nM) despite…

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Topics & keywords

Topics
Keywords
  • Protein design
  • Computational biology
  • Chemistry
  • Combinatorial chemistry
  • Biochemistry
  • Protein structure
  • Biology
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