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ACS Infect Dis. 2015 Apr 10;1(4):157-167. Epub 2015 Mar 2.

Plasmodium IspD (2-C-Methyl-D-erythritol 4-Phosphate Cytidyltransferase), an Essential and Druggable Antimalarial Target.

Author information

1
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
2
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
3
College of Medicine, University of Toledo, Toledo, Ohio 43614, United States.
4
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K.
5
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Abstract

As resistance to current therapies spreads, novel antimalarials are urgently needed. In this work, we examine the potential for therapeutic intervention via the targeting of Plasmodium IspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase), the second dedicated enzyme of the essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis. Enzymes of this pathway represent promising therapeutic targets because the pathway is not present in humans. The Malaria Box compound, MMV008138, inhibits Plasmodium falciparum growth, and PfIspD has been proposed as a candidate intracellular target. We find that PfIspD is the sole intracellular target of MMV008138 and characterize the mode of inhibition and target-based resistance, providing chemical validation of this target. Additionally, we find that the Pf ISPD genetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme. This work provides compelling support for IspD as a druggable target for the development of additional, much-needed antimalarial agents.

KEYWORDS:

IspD; MEP pathway; MMV008138; homology model; malaria; plasmodium

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