Imidazolopiperazines (IZPs) are a novel class of antimalarial drug in clinical development for the treatment of uncomplicated malaria and malaria prophylaxis. IZPs eliminate blood stage infections and both prevent asymptomatic malaria development and malaria transmission in animal models of malaria. One member of the class has been tested in early clinical trials and is well-tolerated by humans when administered orally. Although parasite resistance to IZPs is conferred by mutations in the Plasmodium falciparum gene encoding the parasite P. falciparum cyclic amine resistance locus (PfCARL), the mechanism of action of the IZP's is not well understood. Further studies on how the IZPs work are therefore needed, We propose to use a suite of genomic methods including metabolomics, transcriptomics and other genome-wide methods to study how IZPs act against all Plasmodium lifecycle forms that parasitize humans, with the goal of identifying their precise target. Specifically, we will first use metabolomics profiling to examine how parasite metabolic pathways respond to parasite IZP treatment in blood stages. We will then compare these metabolic responses to the IZPs to the transcriptional response to IZP treatment in blood stages, liver stages and gametocytes. We will also perform similar analyses against compounds with known mechanisms of action, in order to identify IZP specific effects. Second, we will probe for any additional targets using a well-established experimental pipeline of in vitro evolution followed by whole genome sequencing. Genes with identified resistance mutations will be associated with the pathways identified by metabolomic and transcriptional profiling to identify putative targets. Finally, we will confirm any putative targets in P. falciparum through a series o functional studies.
Given the continuing emergence of drug resistance in malaria parasites, there is a clear need for new antimalarial drugs. The imidazolopiperazines are very promising antimalarial drugs currently being tested in human trials. We propose to investigate their activity against malaria parasites in order create better antimalarial drugs, to understand how parasites might become resistant and to improve the efficacy of these drugs in humans.
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