Dynamic Chemical Probes with New Modes of Action to Deconvolute Therapeutic Protein-Protein Interaction Networks

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This project will develop a strategy for the development and evaluation of a 'toolkit' of covalent chemical probes for the inhibition of therapeutically-relevant protein-protein interactions (PPIs) that are critical in myriad diseases. These agents will consist of conformationally-preorganised alpha helical peptidomimetic scaffolds armed with electrophilic warheads. The scaffolds may be functionalised to provide complementary contacts for a given protein surface and to form a covalent bond between the mimetic and a nucleophilic amino acid side-chains (N- and O-centred) displayed on the surface of the target protein. The agents will be designed to bind via either a dynamic or irreversible mechanism with the potential for a high-affinity interaction. Their utility as a general method for mediating PPIs will be evaluated against therapeutically important targets using proteomic workflows in collaboration with Drs Rob Ewing and Paul Skipp.