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Development of novel, selective inhibitors of HIF prolydroxylase


In all multi-cellular organisms, oxygen homeostasis represents a fundamental physiological challenge and requires the co-ordinated regulation of an array of genes. Under hypoxic conditions levels of hypoxia inducible factor, a transcription factor, rise and enable transcription of an array of genes involved in the hypoxic response. Under nomadic conditions, levels of HIF are suppressed by the action of oxygen dependent hydroxyls. This project will contribute to the biochemical knowledge and medicinal exploitation of the hydroxyls (HIF PH), which have been recently established as key regulators of cellular oxygen sensing. Selective inhibitors not only for HIF PH in general, but also for tissue specific HIF PH is-enzymes will be designed and tested. Initially, analogues of 2-oxoglutarate for the HIF PH will be synthesised with the aim of mimicking enzyme/sub-co substrate complexes. X-ray crystallography, NMR, UV/vies, mass spectrometry and kinetics will study these complexes. The second phase will involve the design and testing of isohyets inhibitors and will involve a combination of binding to co substrate and substrate binding sites. A series of peptide and peptidomimetic libraries based on the modelled HIF: HIF hydroxyls interactions will be synthesised. By varying the LXXLAP binding motif of the substrate, it should be possible to obtain inhibitors selective towards HIF PH is forms. It is hoped that inhibitors of HIF PHs might be used to activate HIF and enhance angiogenesis in is chemic/ hypoxic disease. Therapeutic possibilities include the induction pro-angiogenesis via HIF PH inhibitors as an alternative to heart by-pass surgery and that inhibitors may be used as a treatment for treatment of anaemia, providing an alternative for the use of expensive recombinant erythropoietin protein. The Oxford group has recently solved the crystal structure of HIF hydroxyls.

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