An interdisciplinary pipeline for progressing cyclic peptides hits to small molecule inhibitors.

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Research questions and objectives:Peptide macrocycle hits can be readily generated against a given target via a variety of methods, however, progressing these molecules to drug-like entities has proven extremely challenging. Our key objective in this project is to convert a cyclic peptide protein-protein interaction inhibitor from hit to lead.The approach:We will use a combination of chemical biology and computational chemistry to determine the binding site of the cyclic peptide hit on its target protein, and develop more potent small molecules. Our primary aim will be to identify the pharmacophore of the active molecule and use this information to derive small molecule inhibitors. At the same time, we will optimise the activity of the cyclic peptide by incorporating non-natural amino acids and altering the peptide backbone.Novel physical sciences content:Meeting the above objectives will require the development of an interdisciplinary pipeline of tools the crosses the boundaries of computation chemistry and chemical biology. This includes developing new approaches to simulating cyclic peptides, gaining a better understanding of the interaction of cyclic peptides with their targets and developing synthetic chemistry approaches for the synthesis of the target molecules.