Disruption of protein:protein interactions can often be achieved with synthetic peptides which are capable of binding their targets with high affinity and specificity. As such, synthetic peptides have long been considered for clinical applications to antagonise or activate cell signalling pathways. In this presentation, I will describe our efforts to target the cell death (apoptosis) pathways regulated by interactions between the pro-death and pro-survival members of the Bcl-2 family. As this pathway is frequently dysregulated in cancer, new strategies to activate the pathway provide a potential avenue for therapeutic application of Bcl-2 antagonists.

Here, I will describe how we have developed highly potent peptide-based ligands that can specifically target particular pro-survival Bcl-2 proteins. Modification of the peptide sequences through incorporation of non-natural amino acids, specifically beta-amino acids, as well as hydrocarbon “staples”, renders them highly stable compared to their natural peptide counterparts, and capable of crossing cell membranes, an important first step in their direct clinical application. High resolution X-ray crystallographic structural data on how such peptides engage their targets will be presented, together with how this information can be used to rationally design new sequences with altered binding profiles. These data have wider application for the design of unnatural peptide ligands for other cellular targets.