Peptide macrocyclization often confers increased stability and cell permeability in addition to constraining the peptide in a bioactive conformation. A major challenge in developing inhibitors for protein-protein interactions (PPIs) is the stabilization of secondary structures necessary for binding large surface areas. Here, we report a broadly applicable strategy for the synthesis of covalently constrained α-helix mimics via backbone-to-tail macrocyclization. This hydrogen bond surrogate approach replaces the native (<i>i → i+4</i>) hydrogen bond at the N-terminus with a covalent C-N bond. Incorporation of this constraint is expected to nucleate α-helix formation, inducing helicity from the N → C terminus. Our strategy is facilitated through the introduction of an α-hydrazino acid residue at the <i>i+4</i> position and leverages the unique reactivity of backbone N-amino groups toward electrophiles. Our design also conserves all native peptide side-chains and is compatible with Fmoc based solid-phase peptide synthesis. Examples of N-amino peptide-based macrocycles targeting biologically relevant helical PPIs will also be presented.

N-amino peptide macrocycles as constrained α-helices

2019 Spring National Meeting

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