Protein–protein interactions within the Bcl-2 family are mediated by the helical BH3 domains of pro-apoptotic family members. To study the mechanism of this BH3 domain–protein interaction, a series of cyclic lactam bridged BH3 peptide analogues were synthesized by a novel combined Fmoc/tBu/Bzl protections strategy. These peptide analogues were studied by circular dichroism spectroscopy and found to adopt highly helical structure. These helical peptides stabilized by a lactam bridge serve as useful models to analyze the structure–function relationship of the pro-apoptotic BH3 domains. Furthermore, the synthetic method for lactam bridge incorporation reported here may find application in studies of other helical structures and development of helix mimics.