Supramolecular Designs on Dynamic Covalent Protein Recognition

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This project describes a strategy for the development of a 'toolkit' of covalent chemical probes for the inhibition of therapeutically-relevant protein-protein interactions (PPIs) that are critical in myriad diseases. The project will develop molecules that have been carefully designed to adopt a particular shape such that they can mimic the recognition of one protein surface by another, bind to the protein, and then carry out a modification on the protein in question to add a new group of atoms to a particular site. The mimic molecules will be configurable to selectively recognise different protein surfaces as desired. The modification will be carried out by a reactive group on the mimic molecules containing a boron "acceptor" and they will be targeted to modify the side-chain of a specific amino acid on the protein in question - usually one containing an oxygen or nitrogen atom "donor". This 'toolkit' of chemical probes (the mimics) represents a fundamentally new way of targeting non-enzymatic proteins. The agents will be tuneable to bind via either a dynamic or irreversible covalent mechanism. Their utility as a general method for mediating therapeutically-relevant protein-protein interactions (PPIs) will be evaluated using a particular protein system (Hif1alpha/p300) that is important in the hypoxic response and in many solid-tumour cancers. Beyond their use as disruptors of PPIs the approach holds great promise for: (i) mediating protein misfolding, (ii) site-specific protein labelling, (iii) bio imaging, (iv) tumour targeting, (v) therapeutic depletion, and (vi) protein mapping.