Synthesis and β-sheet propensity of constrained N-amino peptides

The stabilization of beta-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable beta-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between alpha-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on beta-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong beta-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on beta-sheet folding. (C) 2017 Elsevier Ltd. All rights reserved.