N-terminal mercaptoproline capping with a cysteine cross-link stabilizes peptide helices to engage MDM2 inside cancer cells
- Short peptides seldom keep a stable helix, hampering intracellular protein–protein interaction targeting; the authors cap the N-terminus with 4-mercaptoproline.
- A covalent bridge to an internal cysteine preorganizes the backbone and encourages helix propagation.
- Adjusting residue stereochemistry and linker composition improved helicity, uptake, protease stability and MDM2 binding, with reduced cancer cell viability and migration.
💡 Points Based on the abstract
All-hydrocarbon staples tend to add greasy bulk that hurts solubility; here the N-terminal cap does double duty as helix nucleator and cross-link anchor, which is neater. For an MDM2 p53-mimetic I'd still want the thiol bridge's stability in cytosol and resistance to reduction checked, but it's a cheaper handle than another staple screen.