Structure-based design of new Cytochrome bc1 inhibitors to combat parasitic infections

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Parasitic organisms such as Plasmodium falciparum- responsible for malaria, and Toxoplasma gondii- responsible for toxoplasmosis, cause widespread disease and morbidity, and new antiparasitic drugs are needed to combat the general rise in resistance to all currently used antiparasitic therapies. A validated target in both of these parasites is the cytochrome bc1 complex, which is a key mitochondrial enzyme that catalyses the transfer of electrons in order to maintain the membrane potential of mitochondria. The aim of this project is to translate our existing structural knowledge of bovine bc1 to the parasite-derived cytochrome bc1 system by solving the first ever Toxoplasma bc1 structure. This will be used to primarily design new potent and selective protozoan inhibitors but will also contribute to the advancement of existing compound series in development at Leeds. This will provide a mix of techniques which will be a powerful approach to fully characterising inhibitor binding to bc1 and developing a series of more potent inhibitors.Via existing collaborators (Prof. Rima McLeod, University of Chicago), we also have access to T. gondii strains represting various life cycle forms, which will enable us to establish the potential of our small molecule bc1 inhibitors as antiparasitic drug leads.The student will be trained in advanced structure-based molecular design, synthetic organic/medicinal chemistry, as well as crystallographic, biochemical and biophysical methods and use the most advance Synchrotron sources like DIAMOND, SOLEIL and SPRING-8 for experiments. The research environments in both of the collaborating institutions provides an ethos that encourages the breaking down of traditional disciplinary barriers and encourages the development of thematic networks of research groups. At Leeds, this approach is a central feature within the world-leading Astbury Centre for Structural Molecular Biology (both Leeds supervisors are members) and the student will be embedded within an environment that offers robust specific training in all of the above areas in addition to a well-developed postgraduate training programme designed to enhance a broader range of skills. This approach to postgraduate training is mirrored within the Institute of Integrative Biology (IIB) at Liverpool which has been highly successful in integrating evolutionary biology with genomic and proteomic technologies, environmental biology with post-genomics and clinical microbiology. Structural Biology is a cross-cutting activity that bridges several institutes of the Faculty as well as having engaging programmes with medicinal chemists and the world renowned Liverpool School of Tropical Medicine