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Proteomimetic Foldamers: Towards Future Therapeutics and Designer Enzymes

Final Report Summary - PROTEOFOLD (Proteomimetic Foldamers: Towards Future Therapeutics and Designer Enzymes)

Traditionally, small molecule drugs act on mis-functioning cellular components through “lock and key” type molecular recognition; the pharmaceutical industry, has, over many years developed competence in the design and chemical synthesis of molecules capable of achieving this type of molecular recognition. However, many biological targets are considered “undruggable” because they exert their effects through protein-protein interactions (PPIs) and it is not clear how the 'hand-gripping-a-ball' type recognition that occurs in PPIs, can be replicated using small molecules. The size of the human PPI interactome is estimated to comprise as many as ~650,000 distinct pairwise interactions. The ability to control and modulate PPIs is therefore of great significance to medical diagnostics of health or disease and molecular therapeutics. The global market size for molecular therapeutics is £200+ billion/year and growing. Of this, only a minute fraction currently comes from small molecules that modulate PPIs, which is astonishing when one realizes that these interactions account for the majority of potential targets. Discovering small molecule inhibitors of PPIs is therefore a major challenge considered to be one of the greatest problems facing chemical biology today.
The Proteofold project aimed to develop an improved “rule-based” approach to identity inhibitors of PPIs – its goals were to do so, by taking inspiration from nature and constructing molecules (which we term proteomimetics) that look and function like components of natural proteins. In a wider context, the project therefore sought to establish “if we can build molecular entities of comparable complexity to natures own functional architectures using non-natural building blocks”. During the project we developed new synthetic methodology for the chemical synthesis of libraries of multiple different proteomimetics – this synthetic methodology has had some uptake amongst the synthesis community already and is likely to be used more widely in future.
In tandem we developed the tools, systems and assays necessary to test the ability of our proteomimetics to act as inhibitors of PPIs. Excitingly, for several series of proteomimetic compounds we identified potent inhibitors of several protein-protein interactions involved in cancer development and progression. We were able to show these compounds act selectively and with good efficacy on their target and interfere with the targets’ signaling pathway in cells. The targets included p53-hDM2 and Mcl-1/BH3. p53 is the major tumor suppressor protein in humans acting as a gatekeeper to identify and repair damaged cells or target them for programmed cell death should they be irreparable. p53 misfunctions in over 50% of human cancers. hDM2 is a negative regulator of p53 that misfunctions in around 10% of human cancers. The p53-hDM2 interaction therefore represents a target of significant interest to every pharmaceutical company in the world. Similarly, Mcl-1 plays a major role in the process of apoptosis (the process of programmed cell death) and is found to be mis-regulated in areas of unmet medical need e.g. pancreatic cancer. Our results therefore provided proof-of-concept that a “rule-based” approach for inhibition of PPIs is plausible. Ongoing studies are directed towards exploring the translation opportunities that have arisen through the Proteofold project by application of our approach to other therapeutically relevant pharmaceutical targets and the development of small molecule screening technologies.