New Insight into Isoprenoids Biosynthesis Process and Future Prospects for Drug Designing in Plasmodium

Abstract

The MEP (Methyl Erythritol Phosphate) isoprenoids biosynthesis pathway is an attractive drug target to combat malaria, due to its uniqueness and indispensability for the parasite. It is functional in the apicoplast of Plasmodium and its products get transported to the cytoplasm, where they participate in glycoprotein synthesis, electron transport chain, tRNA modification and several other biological processes. Several compounds have been tested against the enzymes involved in this pathway and amongst them Fosmidomycin, targeted against IspC (DXP reductoisomerase) enzyme and MMV008138 targeted against IspD enzyme have shown good anti-malarial activity in parasite cultures. Fosmidomycin is now-a-days prescribed clinically, however, less absorption, shorter half-life, and toxicity at higher doses, limits its use as an anti-malarial. The potential of other enzymes of the pathway as candidate drug targets has also been determined. This review details the various drug molecules tested against these targets with special emphasis to Plasmodium. We corroborate that MEP pathway functional within the apicoplast of Plasmodium is a major drug target, especially during erythrocytic stages. However, the major bottlenecks, bioavailability and toxicity of the new molecules needs to be addressed, before considering any new molecule as a potent antimalarial.

Characterization of 1-deoxy-D-xylulose 5-phosphate synthase (DXS) protein in Andrographis paniculata (Burm.f.) Wall. ex. Nees: A in silico appraisal

“…The active site information and super imposed ligands in the ligand binding site was depicted in Figure 16, respectively. This present finding has given more insights on the ligand binding interactions to design drugs in credence with the observations earlier (Saggu et al, 2016;Naz et al, 2017;Goswami, 2017).…”

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

“…More recently, an entire subclass of isoprenoids called monoterpenes, typically found in plants, were discovered and are believed to function as volatile chemoattractants for mosquitoes [50]. While the MEP pathway has received attention as an attractive source of potential drug targets [51,52], the identity and essentiality of the full complement of isoprenoids generated by the parasite remains to be fully elucidated. Isoprenoids are the most abundant class of small molecules [53,54] and further discovery of these compounds is likely to provide additional insights into parasite biochemistry and may allow for the identification of additional druggable pathways.…”

Apicoplast Journey and Its Essentiality as a Compartment for Malaria Parasite Survival

“… Flowchart representation of apicoplast MEP pathway adapted from Saggu, 2016 . Isoprenoids are derived from the basic 5-carbon isoprenoid building blocks of IPP and its isomer, DMAPP.…”