Abstract
Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.
Highlights
Falciparum malaria is a well-known major killer, causing approximately one million deaths per year and 300–500 million clinical cases [(WHO 2010) World malaria report
The malaria parasite belongs to apicomplexan phylum and has a plastid-like structure “apicoplast.” The metabolic pathways in apicoplast differ from the host and apicoplast opens up new possibilities of targeting P. falciparum
Parasites lacking an apicoplast can grow in the presence of isopentenyl pyrophosphate, demonstrating that isoprenoids are the only metabolites produced in the apicoplast which are needed outside of the organelle
Summary
Falciparum malaria is a well-known major killer, causing approximately one million deaths per year and 300–500 million clinical cases [(WHO 2010) World malaria report. The “cyclisation reactions” are unknown in malaria parasites; rearrangements and oxidation of the carbon skeleton are responsible for the enormous structural diversity They are produced from the condensation of the same precursors in all organisms (isopentenyl pyrophosphate and dimethylallyl diphosphate), the evolutionary origin of their biosynthesis remains controversial. The nonmevalonate pathway of isoprenoid biosynthesis is essential in eubacteria (not all) and P. falciparum As this pathway is absent in humans, there is a great interest in targeting the enzymes of nonmevalonate metabolism for antiparasitic drug development. Fosmidomycin is known to inhibit the deoxyxylulose phosphate reductoisomerase (DXR) enzyme of isoprenoid biosynthesis from multiple pathogenic organisms. The work by Brown et al (2010) demonstrated that three enzymes in the pathway (Dxr, IspD, and IspF) are all required for in vitro growth of M. tuberculosis [4]. An insight into host-parasite genetic polymorphisms is presented
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