Design and synthesis of novel mechanism-based inhibitors of IDO1

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The context of the researchThis project will examine the synthesis of novel tryptophan mimetic amino acids as potential mechanism-based inhibitors of indoleamine 2,3-dioxygenases. These enzymes are of significant interest in a range of diseases, in particular due to the observation of immunosuppression resulting from high activity in over-expressing tumours. The synthesis of novel, stereo-defined substrate derivatives and transition state mimics will allow more detailed study of the enzyme mechanism, with compounds designed to trap or intercept key reactive intermediates in the proposed reaction cascade, potentially leading to new classes of drugs targeting these enzymes. Aims and objectivesTo develop and apply synthetic routes/methods for the preparation of a range of novel tryptophan analogues (PhD student). To study the activity of the compounds prepared against isolated indoleamine 2,3-dioxygenases and in tumour cell models (Celentyx). To use the data generated on compounds to inform the design of further chemical tools, and to develop and apply synthetic routes/methods for the preparation of these tools (PhD student).Novelty of the research methodologyThis project will involve the development of new synthetic routes and methods. The compounds prepared will represent a wholly novel approach to inhibition of indoleamine 2,3-dioxygenases, a key target in the emerging field of immuno-oncology.Alignment to EPSRC's strategies and research areas - novel research within the EPSRC remitWithin the EPSRC portfolio, this proposal falls within both the Physical Sciences Theme and Healthcare Technologies Theme, straddling the research areas of Synthetic organic chemistry and Chemical biology and biological chemistry.Potential applications and benefitsUK synthetic organic chemistry underpins the pharmaceutical, fine chemical and agrochemical industries, which are well represented in the UK. This project will maintain this strength, delivering a highly trained synthetic organic chemist well placed to enter the chemical industry or academia. If successful, the novel class of indoleamine 2,3-dioxygenase inhibitors prepared will have utility as tool compounds, leads and ultimately potentially therapies - offering significant benefit to patients and accompanying economic benefit to the UK. The synthetic methodology developed will have potential utility for other researchers working on amino acids, peptides or other biologically active compounds. The novel amino acid mimics prepared will be tested for activity in other settings, e.g. through Lilly PD2 and in Birmingham's internal antibiotic screens. Any companies or collaborators involvedThe project is co-funded by Celentyx, an SME with active research interests in immuno-oncology.