Strategy and Effects of Polyproline Peptide Stapling by Copper(I)‐Catalyzed Alkyne–Azide Cycloaddition Reaction

Polyproline is a unique type of peptide that has a stable, robust, and well‐defined helical structure in an aqueous environment. These features have allowed polyproline to be used as a nanosized scaffold for applications in chemical biology and related fields. To understand its structural properties and to expand the applications, this secondary structure was tested systematically by stapling the peptide at different locations with staples of various lengths. Using the efficient copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC), we successfully prepared stapled polyproline and investigated the impact of this peptide macrocyclization through circular dichroism analysis. Whereas the stapling seems to have no significant effect on polyproline helix II (PPII) conformation in water, the location and the length of the staple affect the transformation of conformation in n‐propanol. These results provide valuable information for future research using peptide stapling to manipulate polyproline conformation for various applications. Twisting the helix: Polyproline′s stable, well‐defined helical structure has allowed it to be used as a nanosized scaffold for applications in chemical biology and related fields. To test this secondary structure systematically, polyproline was stapled at different locations with staples of various lengths by CuAAC, and the impact of this macrocyclization was investigated by CD.