Intrastrand Peptide Staples That Promote β-Sheet Folding, Self-Assembly, and Amyloid Seeding.

ABSTRACT: Side chain stapling of cysteine (Cys) residues offers convenient entry into constrained peptides with enhanced bioactivity and bioavailability. Despite its widespread application in the constraint of α-helical, PPII, and loop conformations, the stabilization of β-sheet folds via intrastrand side chain Cys stapling remains largely unexplored. Here, we demonstrate that i→i+2 stapling with E-butenyl, butynyl, and m-xylyl linkers significantly enhances the folded population of two distinct β-hairpin model peptides. High-resolution NMR structures reveal that these staples support canonical β-sheet backbone torsions and stabilize cross-strand interactions. Leveraging the maintenance of intact backbone hydrogen-bonding edges, we employed i→i+2 side chain

SUBMITTER: Dangi A 

PROVIDER: S-EPMC12616677 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature