Target evaluation of deoxyhypusine synthase from Theileria parva the neglected animal parasite and its relationship to Plasmodium

Njuguna, James Thujon; Koschitzky, Imke von; Gerhardt, Heike; Lämmerhofer, Michael; Choucry, Ali; Pink, Mario; Schmitz-Spahnke, Simone; Bakheit, Mohammed A.; Strübe, Christina; Kaiser, Annette

doi:10.1016/j.bmc.2014.05.007

Cited by 8 publications

(10 citation statements)

References 41 publications

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“…Currently, the Malaria Box has been screened against a number of P. falciparum targets and multiple developmental stages (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), as well as other pathogens (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These studies have identified compounds in the Malaria Box with efficacy against specific metabolic processes, such as the thioredoxin system (9), isoprenoid biosynthesis (14,30), and aminopeptidases (11), as well as protein translation (10) and beta-hematin formation (17).…”

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confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

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Jasmeet

et al. 2016

Antimicrob Agents Chemother

130

196

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The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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mentioning

confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

Painter

Jasmeet

et al. 2016

Antimicrob Agents Chemother

130

196

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“…In this study, we screened the MMV Malaria Box for compounds that might inhibit P. marinus proliferation in vitro , an approach that has been successfully used to identify compounds against other protozoan parasites [19] – [21] . In our previous study, the effect of the drugs on P. marinus proliferation was evaluated at days 2, 4, and 8 post-exposure; however, it was at day 4 post-exposure when the inhibitory effect(s) of most drugs tested became apparent [13] .…”

Section: Resultsmentioning

confidence: 99%

“…Government agencies, drug companies, and non-profit organizations have screened multiple compound libraries against Plasmodium falciparum resulting in the Medicines for Malaria Venture (MMV) Malaria Box ( http://www.mmv.org/malariabox ) [16] . This compound library is being used to find inhibitors of defined parasite life stages [17] , [18] , to describe mechanisms of action [19] , and to find active compounds against other protozoan parasites [20] , [21] . Here, we followed similar approach and tested the MMV Malaria Box for the discovery of novel hits against Perkinsus using an adenosine tri-phosphate (ATP) content-based assay to test P. marinus proliferation growth [13] .…”

Section: Introductionmentioning

confidence: 99%

Identification of MMV Malaria Box Inhibitors of Perkinsus marinus Using an ATP-Based Bioluminescence Assay

Resto

Robledo

2014

PLoS ONE

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“Dermo” disease caused by the protozoan parasite Perkinsus marinus (Perkinsozoa) is one of the main obstacles to the restoration of oyster populations in the USA. Perkinsus spp. are also a concern worldwide because there are limited approaches to intervention against the disease. Based on the phylogenetic affinity between the Perkinsozoa and Apicomplexa, we exposed Perkinsus trophozoites to the Medicines for Malaria Venture Malaria Box, an open access compound library comprised of 200 drug-like and 200 probe-like compounds that are highly active against the erythrocyte stage of Plasmodium falciparum. Using a final concentration of 20 µM, we found that 4 days after exposure 46% of the compounds were active against P. marinus trophozoites. Six compounds with IC50 in the µM range were used to compare the degree of susceptibility in vitro of eight P. marinus strains from the USA and five Perkinsus species from around the world. The three compounds, MMV666021, MMV665807 and MMV666102, displayed a uniform effect across Perkinsus strains and species. Both Perkinsus marinus isolates and Perkinsus spp. presented different patterns of response to the panel of compounds tested, supporting the concept of strain/species variability. Here, we expanded the range of compounds available for inhibiting Perkinsus proliferation in vitro and characterized Perkinsus phenotypes based on their resistance to six compounds. We also discuss the implications of these findings in the context of oyster management. The Perkinsus system offers the potential for investigating the mechanism of action of the compounds of interest.

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“…For this purpose, derivatization of the amino acids in the protein hydrolysate was necessary. Initially, a relative quantification was employed to derive information on the inhibitory activity because a hypusine standard was not available (Atemnkeng et al 2013;Njuguna et al 2014). Thus, deoxyhypusine was quantified with external calibration and hypusine was estimated via the peak area ratio assuming an identical detector response factor.…”

Section: Gc/ms Methods For Hypusine Determinationmentioning

confidence: 99%

“…Two different procedures of processing the GC/MS data were employed to analyze the samples. The first method, which was previously described (Atemnkeng et al 2013;Njuguna et al 2014), leads to a relative quantification of the amino acids in % within a sample by comparing the peak areas of the analytes. For obtaining insight into the absolute inhibition of P. falciparum DOHH by the compounds of interest, a GC/MS method using hypusine (for synthesis as described above) and deoxyhypusine as standards as well as norvaline (Sigma-Aldrich, Munich, Germany) as an internal standard was established, which allows quantification of hypusine in the pmol/µL concentration range.…”

Section: Figmentioning

confidence: 99%

New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential

et al. 2015

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Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme required for hydroxylation of the aminobutyl side chain of deoxyhypusine in eukaryotic translation initiation factor 5A (eIF-5A), the second step in hypusine biosynthesis. DOHH has been recently identified in P. falciparum and P. vivax. Both enzymes have very peculiar features including E-Z type HEAT-like repeats and a diiron centre in their active site. Both proteins share only 26 % amino acid identity to the human paralogue. Hitherto, no X-ray structure exists from either enzyme. However, structural predictions based on the amino acid sequence of the active site in comparison to the human enzyme show that four conserved histidine and glutamate residues provide the coordination sites for chelating the ferrous iron ions. Recently, we showed that P. vivax DOHH is inhibited by zileuton (N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea), a drug that is known for inhibiting human 5-lipoygenase (5-LOX) by the complexation of ferrous iron. A novel discovery program was launched to identify inhibitors of the P. falciparum DOHH from the Malaria Box, consisting of 400 chemical compounds, which are highly active in the erythrocytic stages of Malaria infections. In a first visual selection for potential ligands of ferrous iron, three compounds from different scaffold classes namely the diazonapthyl benzimidazole MMV666023 (Malaria Box plate A, position A03), the bis-benzimidazole MMV007384 (plate A, position B08), and a 1,2,5,-oxadiazole MMV665805 (plate A, position C03) were selected and subsequently evaluated in silico for their potential to complex iron ions. As a proof of principle, a bioanalytical assay was performed and the inhibition of hypusine biosynthesis was determined by GC-MS. All tested compounds proved to be active in this assay and MMV665805 exhibited the strongest inhibitory effect. Notably, the results were in accordance with the preliminary quantum-mechanical calculations suggesting the strongest iron complexation capacity for MMV665805. This compound might be a useful tool as well as a novel lead structure for inhibitors of P. falciparum DOHH.

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Target evaluation of deoxyhypusine synthase from Theileria parva the neglected animal parasite and its relationship to Plasmodium

Cited by 8 publications

References 41 publications

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Identification of MMV Malaria Box Inhibitors of Perkinsus marinus Using an ATP-Based Bioluminescence Assay

New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential

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