Validating IPCS as an antileishmanial drug target

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Leishmaniasis is an insect vector-borne caused by the protozoan Leishmania spp. that places over 350 million people world-wide at risk. There are greater than 12 million people currently infected resulting in an economic burden that is best characterised by the 2 million DALYs caused by the disease. Current treatment of leishmaniasis is difficult requiring a long, costly course of drug treatment using old drugs with poor safety indications requiring close medical supervision. Moreover, resistance to current antileishmanials is increasingly evident. As such the WHO ranks leishmaniasis as one of the world's most neglected diseases. Collectively this emphasises a major need for new drugs targeting new modes of actions. In recent work we have identified an enzyme, IPCS, from Leishmania that has no direct mammalian equivalent. Having used this enzyme to develop biochemical and cell based assays, we have screened the GSK collection of 1.8M compound for potential inhibitors. Following secondary screening, we have identified 5 compounds with good levels of activity and selectivity for the leishmanial enzyme that also have suitable physicochemical profiles (Lipinski rules) to be explored as leads for new drugs. In this four year PhD project, we will validate IPCS as the drug target both chemically and genetically. The collaboration with MRCT will bring essential industrial expertise, training and facilities, for in silico and lab based medicinal chemistry and PK/PD studies, to the project and will also underpin subsequent efforts to develop these hits into leads for a future PPP funded drug discovery programme. As such this project will help deliver the MRC strategy in Global Health, enabling people to Live a long and Health Life. Moreover, it also meets the MRC strategic aim of Supporting Scientists. Combining training in medicinal chemistry, synthesis compound screening, protein characterisation, molecular biology and parasitology it addresses the crucial skills shortage highlighted by RCUK for highly trained multidisciplinary scientists who represent the next generation of biomedical scientific leaders.