A chemical approach to unravelling how peptide signals mediate cell-cell communication

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Chemical probes are small molecule tools that can help address the historically uneven exploration of biology, stimulating research into previously neglected proteins and contributing to the validation of new drug targets.There are ten times as many microbial cells as human cells in our bodies but how these complex communities function is not well understood. Cells communicate, manipulate and detect each other using a chemical language of small molecule signals. In most cases we do not know how signals are sensed, and identifying the protein sensors of signals in live cells is extremely challenging. Few chemical probes are directed at unravelling host-microbe communication, although molecular understanding of how signals interact with their protein targets is lacking in this field.This project will design novel probes based on small molecule peptide signals and establish general methods to analyse what proteins they interact with. Probes will incorporate a warhead (photoreactive or intrinsically reactive) to trap receptors and a tag to attach labels for analysis. Following initial design and validation of probes, the second objective will be the design of novel features such as selectively cleavable linkages within probes to enable precise determination of the binding sites of probes at their protein targets. Finally, labelling chemistry will be used to transfer chemical functionality to receptors, in order to study receptor localisation in the cell, identify new signals and protein interacting partners.This research will therefore establish an enabling technology for identifying which proteins interact with peptide signals in living cells. This approach will be widely applicable across chemical biology to understand other signal-receptor interactions and will also elucidate specific mechanisms of host-microbe communication. These new biological insights will contribute to our understanding of how human cells interact with resident and invading microbes. Dysfunction of these communities has been linked to numerous diseases, including cancer, diabetes and obesity.This project falls within the EPSRC area of Chemical biology and biological chemistry, and will provide training in organic and peptide synthesis, biochemical methods, and mass spectrometry-based proteomics.