Facile Chemoselective Modification of Thioethers Generates Chiral Center-Induced Helical Peptides

The modulation of protein-protein interactions (PPIs) is a promising way for interrogating disease. Stapled peptides that stabilize peptides into a fixed α-helical conformation via chemical means are important representative compounds for regulating PPIs. The effect of the secondary conformation of peptides on the biophysical properties has not been explicitly elucidated due to the difficulty of obtaining peptide epimers with the same chemical composition but different conformations. Herein, we systematically designed and demonstrated the concept of "Chiral Center-Induced Helicity" (CIH) to stabilize the secondary structure of peptides. By introducing a precise R-configuration chiral center on the side-ring of a peptide, researchers can decisively regulate the secondary structure of peptides. Through the study of CIH peptides, we found that increasing the helicity can significantly enhance the stability of peptides and improve the cell membrane penetrating capability of the peptides. Moreover, the substitution group in the chiral center could contribute to additional interactions with the binding groove, which shows great significance for fragment-based drug design. This chapter will focus on the method involved in this research, including specific protocols of the synthesis and basic characterization of CIH peptides in Subheading 3.1. In addition, we have also extended the concept of CIH to dual-chiral center systems, including sulfoxide-based and sulfonium-based in-tether chiral center peptides, which we will introduce in Subheadings 3.2 and 3.3.