A Review on Plasmodium falciparum-Protein Farnesyltransferase Inhibitors as Antimalarial Drug Targets

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

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Triazole substitution of a labile amide bond stabilizes pantothenamides and improves their antiplasmodial potency

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01436-16 ◽

2016 ◽

pp. AAC.01436-16 ◽

Cited By ~ 6

Author(s):

Vanessa M. Howieson ◽

Elisa Tran ◽

Annabelle Hoegl ◽

Han Ling Fam ◽

Jonathan Fu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Drug Targets ◽

Amide Bond ◽

Serum Enzyme ◽

Pantothenate Kinase ◽

Biochemical Pathways ◽

Stage Parasite ◽

Intraerythrocytic Stage

The biosynthesis of CoA from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide-bearing pantothenate analogues, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactivein vivo. In this study we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with IC50values of ∼50 nM and three others have sub-micromolar IC50values. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with thePlasmodium falciparumpantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA and show that the compound inhibits the phosphorylation of [14C]pantothenate by theP. falciparumpantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase.

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Resistance mutations at the lipid substrate binding site of Plasmodium falciparum protein farnesyltransferase

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2006.11.012 ◽

2007 ◽

Vol 152 (1) ◽

pp. 66-71 ◽

Cited By ~ 18

Author(s):

Richard T. Eastman ◽

John White ◽

Oliver Hucke ◽

Kohei Yokoyama ◽

Christophe L.M.J. Verlinde ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Binding Site ◽

Substrate Binding ◽

Resistance Mutations ◽

Protein Farnesyltransferase ◽

Substrate Binding Site ◽

Falciparum Protein ◽

Lipid Substrate

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Hemoglobin Degrading Proteases of Plasmodium falciparum as Antimalarial Drug Targets

Current Drug Targets ◽

10.2174/1389450116666150304104123 ◽

2015 ◽

Vol 16 (10) ◽

pp. 1133-1141 ◽

Cited By ~ 9

Author(s):

Tabish Qidwai

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Drug Targets

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A specific non-bisphosphonate inhibitor of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites

10.1101/134338 ◽

2017 ◽

Cited By ~ 1

Author(s):

Jolyn E. Gisselberg ◽

Zachary Herrera ◽

Lindsey Orchard ◽

Manuel Llinás ◽

Ellen Yeh

Keyword(s):

Plasmodium Falciparum ◽

Physicochemical Properties ◽

Small Molecule ◽

Antimalarial Drug ◽

Drug Target ◽

Drug Targets ◽

Geranylgeranyl Diphosphate Synthase ◽

Geranylgeranyl Diphosphate ◽

Malaria Parasites ◽

Starting Point

SummaryIsoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.

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In Silico Knockout Screening of Plasmodium falciparum Reactions and Prediction of Novel Essential Reactions by Analysing the Metabolic Network

BioMed Research International ◽

10.1155/2018/8985718 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Jelili Oyelade ◽

Itunuoluwa Isewon ◽

Efosa Uwoghiren ◽

Olufemi Aromolaran ◽

Olufunke Oladipupo

Keyword(s):

Infectious Disease ◽

Plasmodium Falciparum ◽

Metabolic Network ◽

Antimalarial Drug ◽

Drug Target ◽

Drug Targets ◽

New Drugs ◽

Biological Evidence ◽

Essential Reactions ◽

Extensive List

Malaria is an infectious disease that affects close to half a million individuals every year and Plasmodium falciparum is a major cause of malaria. The treatment of this disease could be done effectively if the essential enzymes of this parasite are specifically targeted. Nevertheless, the development of the parasite in resisting existing drugs now makes discovering new drugs a core responsibility. In this study, a novel computational model that makes the prediction of new and validated antimalarial drug target cheaper, easier, and faster has been developed. We have identified new essential reactions as potential targets for drugs in the metabolic network of the parasite. Among the top seven (7) predicted essential reactions, four (4) have been previously identified in earlier studies with biological evidence and one (1) has been with computational evidence. The results from our study were compared with an extensive list of seventy-seven (77) essential reactions with biological evidence from a previous study. We present a list of thirty-one (31) potential candidates for drug targets in Plasmodium falciparum which includes twenty-four (24) new potential candidates for drug targets.

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Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box

Genes ◽

10.3390/genes10060471 ◽

2019 ◽

Vol 10 (6) ◽

pp. 471 ◽

Cited By ~ 6

Author(s):

Xinying Wang ◽

Yukiko Miyazaki ◽

Daniel Ken Inaoka ◽

Endah Dwi Hartuti ◽

Yoh-Ichi Watanabe ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Drug Target ◽

Drug Targets ◽

Tricarboxylic Acid Cycle ◽

Drug Resistant ◽

Quinone Oxidoreductase ◽

Mitochondrial Inner Membrane ◽

Transport Chain ◽

Urgent Task

Malaria is one of the three major global health threats. Drug development for malaria, especially for its most dangerous form caused by Plasmodium falciparum, remains an urgent task due to the emerging drug-resistant parasites. Exploration of novel antimalarial drug targets identified a trifunctional enzyme, malate quinone oxidoreductase (MQO), located in the mitochondrial inner membrane of P. falciparum (PfMQO). PfMQO is involved in the pathways of mitochondrial electron transport chain, tricarboxylic acid cycle, and fumarate cycle. Recent studies have shown that MQO is essential for P. falciparum survival in asexual stage and for the development of experiment cerebral malaria in the murine parasite P. berghei, providing genetic validation of MQO as a drug target. However, chemical validation of MQO, as a target, remains unexplored. In this study, we used active recombinant protein rPfMQO overexpressed in bacterial membrane fractions to screen a total of 400 compounds from the Pathogen Box, released by Medicines for Malaria Venture. The screening identified seven hit compounds targeting rPfMQO with an IC50 of under 5 μM. We tested the activity of hit compounds against the growth of 3D7 wildtype strain of P. falciparum, among which four compounds showed an IC50 from low to sub-micromolar concentrations, suggesting that PfMQO is indeed a potential antimalarial drug target.

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