A chemical proteomic strategy to identify novel drug targets in Plasmodium falciparum and corresponding lead compounds for the development of new antimalarials

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Malaria remains one of the leading causes of morbidity and mortality in the world resulting in over a million deaths every year. In view of the widespread development of drug resistance in the parasite against commonly used drugs, there is a necessity to identify new drug targets and develop new pharmacaphores. In the present joint proposal we will utilize a novel chemical proteomic strategy termed activity based protein profiling (ABPP) to identify new targets in P. falciparum that are either essential for survival, growth or pathogenesis together with their corresponding inhibitors that can be developed as anti-malarial. We will screen small focused libraries of drug like natural product inspired compounds that inhibit the parasite growth and then utilize ABPP as chemical-proteomic approach to identify and the corresponding essential drug targets in P. falciparum. Selected biologically relevant targets identified by these analyses will be cloned and recombinant proteins will be expressed. As preliminary work we have already identified some β-lactone compounds that inhibit parasite growth and also identified their potential protease targets in the parasite. Detailed in vitro interaction studies and enzyme activity inhibition studies will be carried out using the recombinant proteins and targeting compounds. Derivatives of these compounds will be designed to identify molecules of higher affinity binding/activity inhibition and higher efficacy to inhibit parasite growth. Selected compounds will be further assessed for their ability to inhibit growth of parasites in a mouse-malaria model.