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

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Cyclic peptides are increasingly used for hit discovery against challenging targets such as protein-protein interactions. There are several advantages to the cyclic peptide scaffold, such as resistance to proteolysis and limited conformational freedom conferred by backbone cyclization, which yields molecules that engage their targets with high selectivity and affinity. However, despite these advantages, the development of small molecule drugs from cyclic peptides remains extremely challenging. There is therefore a need for new approaches that enable the progression of cyclic peptides to drug-like compounds and toward the clinic.This project is a collaboration between the laboratories of Professor Ali Tavassoli and Professor Jonathan Essex. The Tavassoli lab have expertise in the discovery and development of several first in class cyclic peptide protein-protein interaction inhibitors. The Essex lab are experienced in the development and application of computer simulation methodology to biological systems, with a particular emphasis on protein-ligand binding. The chemical biology aspect of this project will involve the synthesis and derivatisation of cyclic peptide inhibitors and conducting a variety of biophysical assays on these molecules, moving towards synthesising and testing derived small molecule inhibitors. The molecular modelling component of this project will involve combining a number of techniques, both ligand-based and structure-based, to identify, optimise and derivatise cyclic peptides leads into small molecules.The multidisciplinary nature of the project will provide outstanding training for the successful applicant. They will benefit from the existing expertise of the Tavassoli and Essex laboratories, receiving training in a wide variety of techniques and disciplines, and becoming expert in a range of experimental and modelling techniques, a skillset that will undoubtedly leave the students very well placed in terms of finding future positions.