Designing helical peptide inhibitors of protein–protein interactions

•Protein interactions mediated by helices can be inhibited with designed peptides.•Peptides must bind tightly and selectively, resist proteolysis and enter cells.•Library methods, modeling, and modification chemistry should be integrated in design.•Targets of recent interest include coiled coils, Bcl-2 proteins, MDM2, and HIV gp41. Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of studies report novel helical peptide inhibitors of protein–protein interactions. New techniques have been developed for peptide design and for chemically stabilizing peptides in a helical conformation, which frequently improves protease resistance and cell permeability. We summarize advances in peptide crosslinking chemistry and give examples of peptide design studies targeting coiled-coil transcription factors, Bcl-2 family proteins, MDM2/MDMX, and HIV gp41, among other targets.