Stretching Peptides

Advances in the modulation of protein-protein interactions (PPIs) enable the characterization of PPI networks that govern disease mechanisms and guide the design of novel therapeutics and probes. These PPIs are often characterized by complementary binding to shallow protein surfaces that are challenging to target using standard methods for high-affinity small molecule ligand generation. Compared to linear peptides, synthetically constrained epitopes provide an energetic advantage for binding PPI surfaces by decreasing unbound-state entropy. Such peptide stapling strategies promoting α-helix and β-hairpin structures are well developed. However, approaches for accessing common extended backbone structures are limited. Here we demonstrate the incorporation of a rigid, linear, diyne brace between side chains at the i to i+2 positions to generate a family of low molecular weight peptide macrocycles adopting extended backbones. We show by NMR and DFT studies that these ‘stretched peptides’ adopt rigid and stable conformations in solution which can be tuned to explore a wide range of extended peptide conformational space, including those inherent to β-strands and polyproline II (PPII) helices. The formation of the diyne brace is accomplished in excellent conversions (>95%) and is amenable to high throughput synthesis. The minimalist structure-inducing tripeptide core (< 300 Da) is amenable to further synthetic elaboration to optimize bioactivity and pharmacokinetics. We showcase the utility of diyne-braced peptides with the synthesis of macrocyclic inhibitors of bacterial signal 1 peptidase.