Journal
ACS INFECTIOUS DISEASES
Volume 1, Issue 4, Pages 157-167Publisher
AMER CHEMICAL SOC
DOI: 10.1021/id500047s
Keywords
IspD; MEP pathway; MMV008138; plasmodium; malaria; homology model
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Funding
- Children's Discovery Institute of St. Louis Children's Hospital
- NIH/NIAID [R01 AI103280]
- Basil O'Connor Starter Scholar Award (March of Dimes)
- Clinical Scientist Development Award (Doris Duke Charitable Foundation)
- NIH Infectious Disease Training [AI007172]
- Stephen I. Morse Graduate Fellowship
- Engineering and Physical Sciences Research Council
- Society for Pediatric Research and Alpha Omega Alpha Medical Honor Society
- NIH MSTP training [GM007200-38]
- Beckman Young Investigator Award from Arnold and Mabel Beckman Foundation
- Washington University
- Engineering and Physical Sciences Research Council [1231289] Funding Source: researchfish
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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 PfISPD 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.
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