N-Terminal 4-Mercaptoproline Capping for Peptide α-Helix Stabilization and Intracellular Protein–Protein Interaction Modulation

Abstract Peptide helices show encouraging promise for modulating intracellular protein–protein interactions, but short peptides often lack stable α-helical conformation. We report an N-terminal 4-mercaptoproline (4MP) capping strategy that stabilizes α-helices via covalent cross-linking between N-terminal 4MP and an internal cysteine. This approach preorganizes the backbone and promotes helix propagation. Furthermore, optimizing 4MP stereochemistry and the cross-linker composition enhances α-helicity, cellular uptake, proteolytic stability, and MDM2 binding, thereby suppressing cancer cell viability, proliferation, and migration.