Converting natural product leads into structure- and ligand-based drug discovery campaigns against leishmaniasis and Chagas' disease

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The neglected parasitic diseases, visceral leishmaniasis (VL), and Chagas' disease (CD), together cause an estimated 50,000 deaths annually world-wide. Most of the people affected by these terrible diseases are amongst the poorest members of society and often live in remote rural areas. Despite this death toll, the current treatments available are inadequate for many reasons. These problems include side effects, compounds not working very effectively, resistance to current drugs and the requirement for intravenous administration or repeated injections which are not suitable for the rural environments where these diseases are typically found. Consequently, the development of new, effective and safe oral drugs provides an opportunity to save many lives and improve the quality of life for whole regions of the developing world, through the reduction of the morbidity, mortality and the economic consequences of these diseases. Unfortunately there are very few compounds being developed for VL and CD.In this proposal we aim to identify potential new targets for drug discovery programmes. These are typically enzymes, which are vital to the life of the parasites that cause the diseases. We aim to identify these start points by testing natural products against the parasites. For those natural products that kill the parasites, we will then find out how the compounds are killing the parasites. Natural products are chemical compounds that are found from natural sources, such as plants and bacteria. They often have unique chemical structures, that have not been made before by humans and are difficult to make synthetically. Therefore they provide good tools to identify potential drug targets that often would not be found by other means. Once we have identified the molecular target (enzymes) we can then carry out a drug discovery programme, either by using these natural products as starting points or using conventional drug discovery approaches to find inhibitors of the enzyme and then optimise them into potential drugs.An established, fully integrated team comprised of the University of Dundee and University of São Paulo, São Carlos brings together the broad range of expertise required to discover these much needed drugs. The team combines natural product expertise, world renowned parasitology, expertise in identifying the modes of action of compounds in these parasites, extensive experience developing molecules that can kill the parasites, and the substantial expertise and infrastructure required to develop drug candidates suitable for progress toward clinical trials.