Stapled Peptide
A peptide stabilised by a synthetic chemical bridge (staple) across adjacent turns of its helical structure. Stapling constrains the peptide in its bioactive conformation, improves resistance to proteolysis, and can enhance cell membrane penetration. Stapled peptides are an active area of drug development.
Technical Context
Stapled peptides use olefin metathesis chemistry (ruthenium-catalysed ring-closing metathesis, typically using Grubbs catalysts) to create an all-hydrocarbon crosslink between non-natural amino acids (typically alpha-methyl, alpha-alkenyl amino acids) placed at positions i, i+4 (one helix turn) or i, i+7 (two helix turns) on the same face of an alpha-helix. The hydrocarbon staple: constrains the peptide in its alpha-helical bioactive conformation (increasing binding affinity by reducing the entropic cost of binding), enhances protease resistance (the crosslink shields adjacent peptide bonds), and can improve cell membrane permeability (the staple increases hydrophobicity and masks backbone polarity). Aileron Therapeutics' ALRN-6924 (targeting MDM2/MDMX to reactivate p53 in cancer) is the most advanced clinical-stage stapled peptide. The technology is particularly valuable for disrupting protein-protein interactions — traditionally considered 'undruggable' targets.