Peptide Tethering: Pocket-Directed Fragment Screening for Peptidomimetic Inhibitor Discovery

• Published in: Journal of the American Chemical Society Vol. 144; no. 3; pp. 1198 - 1204
• Main Authors: Modell, Ashley E, Marrone, Frank, Panigrahi, Nihar R, Zhang, Yingkai, Arora, Paramjit S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.01.2022; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Drug Discovery; Humans; Ligands; Models, Molecular; p300-CBP Transcription Factors - antagonists & inhibitors; p300-CBP Transcription Factors - chemistry; p300-CBP Transcription Factors - metabolism; peptides; Peptides - chemistry; Peptides - pharmacology; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Physical Sciences; Science & Technology; topography; CBP; TRANSCRIPTION FACTOR-BINDING; LINEAGE LEUKEMIA PROTEIN; HIGH-AFFINITY LIGANDS; STRUCTURAL BASIS; MOLECULAR RECOGNITION; KIX DOMAIN; ALLOSTERIC SITE; HELICAL PROTEIN INTERFACES; SURFACES
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.1c09666

Constrained peptides have proven to be a rich source of ligands for protein surfaces, but are often limited in their binding potency. Deployment of nonnatural side chains that access unoccupied crevices on the receptor surface offers a potential avenue to enhance binding affinity. We recently described a computational approach to create topographic maps of protein surfaces to guide the design of nonnatural side chains [J. Am. Chem. Soc. 2017, 139, 15560]. The computational method, AlphaSpace, was used to predict peptide ligands for the KIX domain of the p300/CBP coactivator. KIX has been the subject of numerous ligand discovery strategies, but potent inhibitors of its interaction with transcription factors remain difficult to access. Although the computational approach provided a significant enhancement in the binding affinity of the peptide, fine-tuning of nonnatural side chains required an experimental screening method. Here we implement a peptide-tethering strategy to screen fragments as nonnatural side chains on conformationally defined peptides. The combined computational–experimental approach offers a general framework for optimizing peptidomimetics as inhibitors of protein–protein interactions.