Macrocyclic peptides are promising inhibitors of challenging drug targets such as intracellular protein-protein interactions. Using cyclisation chemistry to constrain the conformation of a peptide can lead to improvements in its proteolytic stability, target binding affinity and degree of uptake into cells1. Despite this potential, rational design of in vivo efficacious peptides remains a major challenge. Extensive screening is typically required to identify a potential lead candidate, involving variations in the amino acid sequence, structure of the cyclisation linker and its positioning along the peptide.
In this talk, I will introduce a toolbox of functionalised dialkynyl compounds which can be used for efficient and divergent exploration of sequence and linker chemical space. Compounds in this toolbox can trigger macrocyclisation of completely unprotected diazido peptides in a one-step double-click reaction2. The simplicity and biocompatibility of this chemistry enables rapid synthesis and identification of peptides with the desired inhibitory efficacy. I will outline several recent examples of this methodology in action, including the development of inhibitors for the oncogenic tankyrase-axin3, p53-MDM24 and Sld5-Ctf4 protein-protein interactions.
Finally, I will briefly discuss how therapeutic peptide research may benefit from placing greater emphasis on cell-based studies at an early stage, optimising for parameters such as uptake and stability rather than focusing solely on in vitro binding affinity.