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

Publication date: Available online 31 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Matthew P. Sarnowski, Kyle P. Pedretty, Nicole Giddings, H. Lee Woodcock, Juan R. Del Valle
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 -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.

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