The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between α-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 β-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong β-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on β-sheet folding.
Sarnowski, M. P., Pedretty, K. P., Giddings, N., Woodcock, H. L., & Del Valle, J. R. (2018). Synthesis and β-sheet propensity of constrained N-amino peptides. Bioorganic and Medicinal Chemistry, 26(6), 1162–1166. https://doi.org/10.1016/j.bmc.2017.08.017