Activity-based chemical probes for the profiling of cytochrome P450s

PLEASE NOTE THAT THIS PROJECTIS FOR SELF-FUNDED STUDENTS.

Applications are invited from Graduates in Chemistry, Pharmacy and Medicinal Chemistry Master’s level programs to join our group within the School of Medicine, Pharmacy and Health. The project encompasses the synthesis and biological screening of a novel group of cytochrome P450 inhibitor probes.

Cytochrome P450s (CYP450s) constitute a large family of haem-centred, with fundamental roles in the biotransformation of endogenous (steroid hormones, fatty acids, prostaglandins) and exogenous molecules (drugs, environmental chemicals, agrochemicals). As a direct result of their importance, particularly in xenobiotic and drug metabolism, a great deal of research has been conducted into the roles, identification of their sequences and their catalytic mechanism. Whilst a number of CYP450s, particularly human liver CYP450s and extra-hepatic CYP450s (i.e. CYP1A1, CYP1B1 and CYP2W1) have been the subject of intense investigation, much is still to be learnt from these mixed-function oxidases. This reflects the difficulties associated with studying these enzymes as (i) they are encoded by large gene families and their functions cannot be predicted from their gene sequence, (ii) they are difficult to assay, isolate and purify, so classical biochemical methods are often ineffectual in identifying enzymes of interest, (iii) these proteins are membrane bound and often dependent on co-enzymes and co-factors, making them difficult to express as a functional enzymes in cellular systems, and (iv) polymorphisms and epigenetic regulation alter their expression and functional activity. As a result, new approaches to identifying, evaluating and quantifying functionally active CYP450s are of the upmost importance.

As a result, this project will involve the following a.) expand a library of diverse structural cytochrome P450 inhibitors; b.) iterative biological testing of the compound library to new CYP450 enzymes to expand the scope of the probe library. You will undertake the synthesis and in-house testing of these compounds in our world leading facilities here at Durham, where you will have access to state of the art laboratories and analytical equipment.

Potential candidates will require a strong background in chemical synthesis, with background knowledge of microbiological techniques and protein purification being advantageous.