Conformationally Constrained Macrocycles and their Applications

Inhibition of protein-protein interactions (PPIs) represents a significant challenge when applying traditional small molecule drug discovery methods. Stapled peptides are rationally-designed inhibitors of PPIs, in which amino acid side chains are covalently linked to reinforce the optimal conformation for binding a target protein. PPIs play a central role in all biological processes and represent an important target space for pharmacological intervention. Abnormal PPIs can disrupt critical cellular processes and lead to human diseases. Thus, the ability to control and modulate these PPIs could potentially open up a vast array of new molecular therapeutics. However, inhibition of PPIs has proved to be a significant challenge when applying traditional small molecule drug discovery methods, due to the large surface area of PPI interfaces, as well as the lack of natural small molecule binder from which to design inhibitors. In contrast, peptides are well suited to bind proteins at PPI interfaces. Unfortunately peptides make poor therapeutic candidates due to their lack of cell permeability and susceptibility to proteolysis. A promising method for circumventing these issues is peptide stapling: the covalent linking of side-chains to lock a peptide into a particular conformation. This research aims to develop novel macrocycles of peptides and peptidomimetics and to apply them in various applications.