A Highly Stable Short α-Helix Constrained by a Main-Chain Hydrogen-Bond Surrogate

Abstract

Herein we describe a strategy for the preparation of artificial α-helices involving replacement of one of the main-chain hydrogen bonds with a covalent linkage. To mimic the CO···H−N hydrogen bond as closely as possible, we envisioned a covalent bond of the type CX−Y−N, where X and Y are two carbon atoms connected through an olefin metathesis reaction. Our results demonstrate that the replacement of a hydrogen bond between the i and i + 4 residues at the N-terminus of a short peptide with a carbon−carbon bond results in a highly stable constrained α-helix at physiological conditions as indicated by CD and NMR spectroscopies. The advantage of this strategy is that it allows access to short α-helices with strict preservation of molecular recognition surfaces required for biomolecular interactions.