TY  - JOUR
AU  - Rettie, Stephen A.
AU  - Juergens, David
AU  - Adebomi, Victor
AU  - Bueso, Yensi Flores
AU  - Zhao, Qinqin
AU  - Leveille, Alexandria N.
AU  - Liu, Andi
AU  - Bera, Asim K.
AU  - Wilms, Joana A.
AU  - Üffing, Alina
AU  - Kang, Alex
AU  - Brackenbrough, Evans
AU  - Lamb, Mila
AU  - Gerben, Stacey R.
AU  - Murray, Analisa
AU  - Levine, Paul M.
AU  - Schneider, Maika
AU  - Vasireddy, Vibha
AU  - Ovchinnikov, Sergey
AU  - Weiergräber, Oliver H.
AU  - Willbold, Dieter
AU  - Kritzer, Joshua A.
AU  - Mougous, Joseph D.
AU  - Baker, David
AU  - DiMaio, Frank
AU  - Bhardwaj, Gaurav
TI  - Accurate de novo design of high-affinity protein-binding macrocycles using deep learning
JO  - Nature chemical biology
VL  - 21
IS  - 12
SN  - 1552-4450
CY  - Basingstoke
PB  - Nature Publishing Group
M1  - FZJ-2026-00658
SP  - 1948 - 1956
PY  - 2025
AB  - 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 (Kd < 10 nM) despite starting from the predicted target structure. X-ray structures for macrocycle-bound myeloid cell leukemia 1, γ-aminobutyric acid type A receptor-associated protein and RbtA complexes match closely with the computational models, with a Cα root-mean-square deviation < 1.5 Å to the design models. RFpeptides provides a framework for rapid and custom design of macrocyclic peptides for diagnostic and therapeutic applications.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s41589-025-01929-w
UR  - https://juser.fz-juelich.de/record/1051977
ER  -