Fine Tuning the Properties of Stapled Peptides by Stereogenic α‐Amino Acid Bridges

Abstract

AbstractPeptide stapling represents a versatile strategy to generate peptide derivatives with stable helical structures. While a wide range of skeletons have been investigated for cyclizing the side chains of peptides, the stereochemical outcomes from the linkers remain to be better understood. In this study, we incorporated α‐amino acids (α‐AAs) as bridges to construct side chain‐stapled analogs of an interleukin‐17A‐binding peptide (HAP) and evaluated the impacts of the staples on the peptide's properties. While all AA‐derived peptidyl staples drastically increase the enzymatic stability of HAP, our results indicate that compared to the D‐amino acid bridges, the L‐AA‐based staples may generate more significant impacts in increasing the helicity and enhancing the interleukin‐17A(IL‐17A)‐binding affinity of the modified peptide. Using Rosetta modelling and molecular dynamics (MD) simulations, we demonstrate that the chirality (L/D) possessed within the AAs substantially influences the conformation of stapled HAP peptides, providing either stabilizing or destabilizing effects. Based on the computational model, a modification of the stapled HAP leads to the discovery of a peptide with further enhanced helicity, enzymatic stability and IL‐17A‐inhibiting ability. This systematic study reveals that chiral AAs can serve as modulatory linkers for optimizing the structures and properties of stapled peptides.