Structural Basis for α-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization.

Automated summary

Efficient optimization of peptide leads into drug candidates often requires further transformation to enhance properties such as bioavailability. Foldamers, specifically oligourea foldamers, have been introduced to reduce the peptide character of protein-protein interaction inhibitors. The study reports X-ray structures of peptide-oligourea hybrids bound to ubiquitin ligase MDM2 and vitamin D receptor, demonstrating their high affinity binding to protein targets.