Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages

Weidner, Thomas; Lucantoni, Leonardo; Nasereddin, Abedelmajeed; Preu, Lutz; Jones, Peter G.; Dzikowski, Ron; Avery, Vicky M.; Kunick, Conrad

doi:10.1186/s12936-017-1839-3

Cited by 12 publications

(11 citation statements)

References 28 publications

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“…Many potential inhibitors that interfere with the CoA biosynthetic pathway in Plasmodium have been reported ( Fletcher and Avery, 2014 ; Fletcher et al., 2016 ; Weidner et al., 2017 ). Although pantothenate analogs such as pantothenol (PanOH), CJ-15,801 ( Saliba and Kirk, 2005 ; Saliba et al., 2005 ; Spry et al., 2005 ), N5-trz-C1-Pan, and N -PE-αMe-PanAm ( Macuamule et al., 2015 ; Howieson et al., 2016 ) were expected to target PanK, they appeared to inhibit other enzymes than PanK.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

Nurkanto

Jeelani

Santos

et al. 2021

Front. Cell. Infect. Microbiol.

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Coenzyme A (CoA) is a well-known cofactor that plays an essential role in many metabolic reactions in all organisms. In Plasmodium falciparum, the most deadly among Plasmodium species that cause malaria, CoA and its biosynthetic pathway have been proven to be indispensable. The first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (PfPanK1 and 2) in this parasite. Here we produced, purified, and biochemically characterized recombinant PfPanK1 for the first time. PfPanK1 showed activity using pantetheine besides pantothenate, as the primary substrate, indicating that CoA biosynthesis in the blood stage of P. falciparum can bypass pantothenate. We further developed a robust and reliable screening system to identify inhibitors using recombinant PfPanK1 and identified four PfPanK inhibitors from natural compounds.

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Section: Discussionmentioning

confidence: 99%

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

Nurkanto

Jeelani

Santos

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Interestingly at 1 μM it potently inhibited both male and female gametogenesis suggesting it targets biology fundamental to both gametocyte sexes. In support of this, TCMDC-124514 has been hypothesized to be a Coenzyme A biosynthesis inhibitor (Weidner et al, 2017) which would both affect energy and lipid metabolism – both fundamental pathways within the parasite. The difference in species activity suggest that TCMDC-124514 is more active against P. falciparum than P. berghei .…”

Section: Discussionmentioning

confidence: 99%

Fueling Open Innovation for Malaria Transmission-Blocking Drugs: Hundreds of Molecules Targeting Early Parasite Mosquito Stages

et al. 2019

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BackgroundDespite recent successes at controlling malaria, progress has stalled with an estimated 219 million cases and 435,000 deaths in 2017 alone. Combined with emerging resistance to front line antimalarial therapies in Southeast Asia, there is an urgent need for new treatment options and novel approaches to halt the spread of malaria. Plasmodium, the parasite responsible for malaria propagates through mosquito transmission. This imposes an acute bottleneck on the parasite population and transmission-blocking interventions exploiting this vulnerability are recognized as vital for malaria elimination.Methods13,533 small molecules with known activity against Plasmodium falciparum asexual parasites were screened for additional transmission-blocking activity in an ex vivo Plasmodium berghei ookinete development assay. Active molecules were then counterscreened in dose response against HepG2 cells to determine their activity/cytotoxicity window and selected non-toxic representative molecules were fully profiled in a range of transmission and mosquito infection assays. Furthermore, the entire dataset was compared to other published screens of the same molecules against P. falciparum gametocytes and female gametogenesis.Results437 molecules inhibited P. berghei ookinete formation with an IC50 < 10 μM. of which 273 showed >10-fold parasite selectivity compared to activity against HepG2 cells. Active molecules grouped into 49 chemical clusters of three or more molecules, with 25 doublets and 94 singletons. Six molecules representing six major chemical scaffolds confirmed their transmission-blocking activity against P. falciparum male and female gametocytes and inhibited P. berghei oocyst formation in the standard membrane feeding assay at 1 μM. When screening data in the P. berghei development ookinete assay was compared to published screens of the same library in assays against P. falciparum gametocytes and female gametogenesis, it was established that each assay identified distinct, but partially overlapping subsets of transmission-blocking molecules. However, selected molecules unique to each assay show transmission-blocking activity in mosquito transmission assays.ConclusionThe P. berghei ookinete development assay is an excellent high throughput assay for efficiently identifying antimalarial molecules targeting early mosquito stage parasite development. Currently no high throughput transmission-blocking assay is capable of identifying all transmission-blocking molecules.

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“…The cytotoxicity of selected antiplasmodial bisindolylcyclobutenediones was determined against THP-1 cells following a protocol described previously [ 54 , 55 , 56 ]. In brief, THP-1 cells were incubated with test compounds in serial compound dilutions in the presence of 0.01% DMSO at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The cytotoxicity of selected antiplasmodial bisindolylcyclobutenediones was determined against THP-1 cells following a protocol described previously [54][55][56]. In brief, THP-1 cells were incubated with test compounds in serial compound dilutions in the presence of 0.01% DMSO at 37 • C. After 48 h, Alamar Blue was added, and after 4 h the fluorescence was read (λ ex = 544 nm, λ em = 590 nm) using a microplate reader.…”

Section: Cytotoxicity Assay On Human Thp-1 Cell Linementioning

confidence: 99%

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

Lande

Nasereddin²,

Alder

et al. 2021

Molecules

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Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

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Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages

Cited by 12 publications

References 28 publications

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

Fueling Open Innovation for Malaria Transmission-Blocking Drugs: Hundreds of Molecules Targeting Early Parasite Mosquito Stages

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

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