Directing protein modification in living systems with bifunctional molecules

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Protein post-translational modifications (PTMs) are chemical changes to the structure of a protein after it has been made in the cell and are typically introduced and/or removed by enzymes. There are over 1000 classes of PTM in the human proteome introduced at over 1 million distinct sites on proteins. PTMs often have a profound effect on protein function and regulate all aspects of biology and underlie or represent opportunities for intervention in every type of disease. Recently, a new drug discovery paradigm has emerged whereby bifunctional molecules induce assembly of complexes which catalyse PTMs de novo, most prominently to induce ubiquitination and degradation of a target protein (so-called 'PROTACs'), a modality recently progressed into clinical trials. Since they co-opt enzyme catalytic functions already present in cells, such drugs can deliver potent biological effects at low occupancy and at sites unrelated to protein function, overturning previous assumptions about what can be achieved with small molecules. Drawing on the deep expertise of the Tate group in the design of chemical tools to understand and exploit PTMs in living systems, a powerful peptide selection platform in the Walport lab, and the world-leading capabilities at MSD in drug discovery and development, you will design, synthesize and develop a new class of bifunctional molecules capable of inducing dramatic changes in protein function and localisation, with profound potential for manipulating biology and modulating disease outcomes.