Inhibitors of Purine Import into Plasmodium falciparum Kill Malaria Parasites
嘌呤输入恶性疟原虫的抑制剂可杀死疟疾寄生虫
基本信息
- 批准号:9000003
- 负责人:
- 金额:$ 68.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-02-01 至 2020-01-31
- 项目状态:已结题
- 来源:
- 关键词:5 fluorouridineAccountingAdenosineAffinityAntimalarialsArtemisininsBindingBinding SitesBiochemicalBiological AssayBiological AvailabilityBiologyBloodCell membraneCell physiologyCessation of lifeChemicalsCombination Drug TherapyCombined Modality TherapyCysteineDNADNA biosynthesisDataDevelopmentDrug KineticsDrug TargetingEconomic BurdenEndoplasmic ReticulumEquilibrative Nucleoside Transporter 1ErythrocytesGeneticGenomeGoalsGrowthGuanineHumanHypoxanthinesIndividualInfectionInosineInvadedKnock-outLibrariesLife Cycle StagesLiverMalariaMass Spectrum AnalysisMediatingModelingMolecular ConformationMusNucleoside TransporterNucleosidesNucleotidesOocystsOralParasitesPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPhasePhosphorylasesPhysiologicalPlasmodiumPlasmodium falciparumPlayProcessProteinsPurine AntagonistPurinesRNA chemical synthesisResistanceResistance developmentRoleRuptureSaccharomyces cerevisiaeSeriesSignal TransductionSiteSoutheastern AsiaSpecificitySporozoitesStagingStarvationStructure-Activity RelationshipTestingTherapeuticTimeToxic effectUridineVariantVirulentWorkXanthinesYeastsadenosine deaminaseartemisininebasecell growthcytotoxicdrug developmentefficacy testingenzyme pathwayhigh throughput screeninghuman diseaseimprovedinhibitor/antagonistkillingsmalaria infectionmutantnovelnovel strategiesnucleobasepreventpublic health relevanceresistance mechanismscaffoldsmall molecule inhibitorstructural biologytargeted treatmenttreatment choiceuptake
项目摘要
DESCRIPTION (provided by applicant): Infection with unicellular eukaryotic Plasmodium species parasites causes malaria. P. falciparum causes the most virulent form of malaria. Currently, artemisinin combination therapy (ACT) is the treatment of choice for infected individuals. The rise of artemisinin resistant P. falciparum in Southeast Asia makes it imperative to develop new antimalarial drugs. Malaria parasites are purine auxotrophs. They transport purine precursors from the host erythrocyte into the parasite via the P. falciparum Equilibrative Nucleoside Transporter 1 (PfENT1). In the parasite, purine salvage pathway enzymes modify the purine precursors to form the nucleotides needed for RNA and DNA synthesis and other cellular processes. At purine concentrations found in human blood (<10 µM), PfENT1 knockout parasites are not viable in culture. Thus, PfENT1 inhibitors may function as potent antimalarial drugs. The goal of this project is to explore the therapeutic hypothesis that inhibition of PfENT1 will kill malaria parasites and provide a novel target for antimalarial drug development. We have developed a simple, robust yeast cell growth assay and used it in a high throughput screen (HTS) to identify PfENT1 inhibitors. 5-fluorouridine (5-FUrd) kills wild type Saccharomyces cerevisiae. Mutant fui1Δ yeast that lack the endogenous plasma membrane purine/uridine nucleoside transporter are 100 times more resistant to 5-FUrd. PfENT1 transports 5-FUrd. In the presence of 125 µM 5-FUrd, PfENT1-expressing fui1Δ yeast will only grow if a PfENT1 inhibitor is present to prevent 5-FUrd uptake. In 384 well plates, the Coefficient of Variation was
<6.2%, Signal Window > 12, and the Z' score > 0.80, indicating a highly robust assay. We screened a 64,500 compound library and identified 171 hits. We tested nine of the top hits in a series of secondary assays. All nine inhibited [3H]adenosine uptake into both PfENT1-expressing yeast and into erythrocyte-free trophozoite stage P. falciparum with IC50 values in the 2 - 40 nM range. The nine compounds, five distinct chemical scaffolds, do not kill yeast but do kill P. falciparum parasites in culture with IC50 values in the 5 - 55 µM range. The goals of this application are 1) to improve the potency and selectivity of the PfENT1 inhibitors through medicinal chemistry; 2) to define the mechanism of action of the inhibitors and their impact on parasite biology and growth at various life cycle stages; 3) to test the efficacy of the inhibitorsin a mouse malaria model; and 4) to identify the inhibitor binding site and the conformation of PfENT1 to which the inhibitors bind. Successful completion of this project will determine the utility of targeting PfENT1 for antimalarial drug development and may identify compounds suitable for further development.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Myles H. Akabas其他文献
Identification Of Channel-lining Residues In The Prokaryotic Proton-gated Cys-loop Receptor Ion Channel From <em>Gloeobacter Violaceus</em>
- DOI:
10.1016/j.bpj.2008.12.780 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Rishi Parikh;Moez Bali;Myles H. Akabas - 通讯作者:
Myles H. Akabas
Length and Composition of the 5HT3A Receptor M3M4 Loop Effects Channel Expression and Desensitization
- DOI:
10.1016/j.bpj.2009.12.698 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Nicole McKinnon;Moez Bali;Myles H. Akabas - 通讯作者:
Myles H. Akabas
M2 Segment Accessibility in The Prokaryotic Proton-Gated Cys-loop Receptor Channel from Gloeobacter Violaceus in Closed and Open States
- DOI:
10.1016/j.bpj.2009.12.704 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Rishi B. Parikh;Moez Bali;Myles H. Akabas - 通讯作者:
Myles H. Akabas
Rigid Motion Near the GABA<sub>A</sub> Receptor α<sub>1</sub> Subunit First Transmembrane Segment Revealed by pCMBS<sup>-</sup> Reactivity in Cysteine-Substituted Mutants During Channel Activation
- DOI:
10.1016/j.bpj.2010.12.1712 - 发表时间:
2011-02-02 - 期刊:
- 影响因子:
- 作者:
Moez Bali;Myles H. Akabas - 通讯作者:
Myles H. Akabas
Myles H. Akabas的其他文献
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{{ truncateString('Myles H. Akabas', 18)}}的其他基金
Inhibitors of Purine Import into Plasmodium falciparum Kill Malaria Parasites
嘌呤输入恶性疟原虫的抑制剂可杀死疟疾寄生虫
- 批准号:
8859480 - 财政年份:2015
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Postbaccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
10516330 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Postbaccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
10356124 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Post-baccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
9418154 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Post-baccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
8433775 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Post-baccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
9180965 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Post-baccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
8996181 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Postbaccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
9889131 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
Einstein Post-baccalaureate Research Education Program
爱因斯坦学士后研究教育计划
- 批准号:
8639586 - 财政年份:2013
- 资助金额:
$ 68.26万 - 项目类别:
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