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

Gagandeep S Saggu,Vishal Saxena,Shilpi Garg,Zarna R Pala

doi:10.3389/fmicb.2016.01421

Gagandeep S Saggu, Vishal Saxena + Show 2 more

Open Access

https://doi.org/10.3389/fmicb.2016.01421

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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.

Highlights

Isoprenoids are structurally and functionally the most diverse group of natural metabolites found in all three domains i.e., eubacteria, archaebacteria and eukarya
Following similar approach for synthesis of reverse analogs, Konzuch et al (2014) showed a new compound 4-[Hydroxy(methyl)amino]1-(4-methoxyphenyl)-4-oxobutylphosphonic acid, to exhibits more than one order of magnitude of activity in comparison to Fos. Another approach has been tried by Haymond et al (2014), where several compounds from resolved crystal structures of M. tuberculosis MEP synthase in complex with Fos were designed, containing an amide-linked or O-linked functional group
The most successful inhibitors identified till date for IspF are non-cytidine-like thiazolopyrimidine derivatives, with high activity against both P. falciparum (IC50 = 9.6 μM) and M. tuberculosis IspF (IC50 = 6.1 μM) (Geist et al, 2010), and the aryl bis-sulphonamide inhibitors showing inhibition of P. falciparum IspF and A. thaliana IspF with IC50 values as low as 1.4 μM and 240 nM, respectively (Thelemann et al, 2015)

Summary

Introduction

Isoprenoids are structurally and functionally the most diverse group of natural metabolites found in all three domains i.e., eubacteria, archaebacteria and eukarya. Following similar approach for synthesis of reverse analogs, Konzuch et al (2014) showed a new compound 4-[Hydroxy(methyl)amino]1-(4-methoxyphenyl)-4-oxobutylphosphonic acid, to exhibits more than one order of magnitude of activity in comparison to Fos. Another approach has been tried by Haymond et al (2014), where several compounds from resolved crystal structures of M. tuberculosis MEP synthase in complex with Fos were designed, containing an amide-linked or O-linked functional group.

Results

Conclusion