Development of inhibitors of P. falciparum cGMP dependent protein kinase (PfPKG) for malaria chemoprevention
开发用于疟疾化学预防的恶性疟原虫 cGMP 依赖性蛋白激酶 (PfPKG) 抑制剂
基本信息
- 批准号:9386266
- 负责人:
- 金额:$ 72.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAllelesAnimalsAntimalarialsAppearanceBackBinding ProteinsBiological AssayBiologyBloodCellsChemicalsChemopreventionChemoprotectionChemoprotective AgentCyclic GMP-Dependent Protein KinasesDataDevelopmentDiseaseDoseDrug TargetingEnsureEnzymatic BiochemistryEnzymesErythrocytesEvaluationFutureGenesGeneticGoalsGrowthHepG2HepatocyteHomologous GeneHumanImidazoleImmune responseIn VitroIncidenceInfectionInfection preventionInvadedIsoxazolesLeadLiverLuciferasesMalariaMeasuresMetabolicModelingMonitorMusOralOrganic ChemistryParasitemiaParasitesPathologyPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePhosphotransferasesPlasma ProteinsPlasmodiumPlasmodium falciparumPlasmodium vivaxPreventionPricePropertyPyrrolesRecombinantsRelapseResistanceRodent ModelSeriesSeveritiesSpecificitySporozoitesStructureStructure-Activity RelationshipTechniquesTestingTimeToxic effectTransgenic Organismsanalogasexualbasecytotoxicity testdesignefficacy testingin vivoin vivo imaging systeminhibitor/antagonistkinase inhibitorliver infectionmouse modelnew therapeutic targetnovelnovel therapeuticspreventscaffoldscreeningtissue/cell culturewater solubility
项目摘要
ABSTRACT
Malaria is caused by the protozoan parasite, Plasmodium. It begins with the infection by Plasmodium
sporozoites of the liver. This step is essential for the expansion of parasite numbers and the subsequent
symptomatic erythrocytic cycle. Inhibition of pre-erythrocytic infection will prevent malaria pathology and
relapses from P. vivax. Current drugs against pre-erythrocytic stages have significant side-effects or are
expensive. Therefore, there is an urgent need for new drugs against pre-erythrocytic stages of Plasmodium.
Our scientific premise is that inhibition of P. falciparum cGMP-dependent protein kinase (PfPKG) will block the
pre-erythrocytic cycle, and impede the erythrocytic cycle. Our hypothesis is based on data demonstrating that
(i) chemical inhibition of PfPKG prevents infection by P. falciparum sporozoites of tissue culture cells, and by P.
berghei sporozoites of mice. (ii) Chemical or genetic inhibition of P. berghei PKG blocks development of
invaded sporozoites into mature, infectious liver stages.
We propose to initiate a medicinal chemistry effort to synthesize and test a new chemical series of PfPKG
inhibitors. Validated hits from this series demonstrate in vitro selectivity for PfPKG, over its human homolog, in
enzymatic activity assays and are activite against the parasite. We propose a medicinal chemistry effort to
optimize molecules from this series to yield potent and PfPKG-selective compounds with whole-cell activity,
acceptable pharmaceutical properties for in vivo testing in mice.
摘要
疟疾是由原生动物寄生虫疟原虫引起的。它始于疟疾的感染
肝脏的子孢子。这一步骤对于寄生虫数量的扩大和随后的
有症状的红细胞周期。抑制红细胞前感染将预防疟疾病理和
间日疟原虫复发。目前针对红细胞前阶段的药物有显著的副作用或
很贵的。因此,迫切需要针对红细胞前期疟原虫的新药。
我们的科学前提是抑制恶性疟原虫cGMP依赖的蛋白激酶(PfPKG)将阻断
红血球前循环,阻碍红血球循环。我们的假设是基于数据表明
(1)PfPKG的化学抑制可防止恶性疟原虫子孢子对组织培养细胞的感染,也可防止恶性疟原虫感染。
小鼠伯氏子孢子。(Ii)化学或遗传抑制伯氏假单胞菌PKG可阻止
侵入子孢子进入成熟的、有感染性的肝脏阶段。
我们建议发起一项药物化学努力,以合成和测试一系列新的PfPKG化学物质
抑制剂。本系列验证的HITS显示了PfPKG的体外选择性,高于其人类同源物,在
酶活性测定和对寄生虫的激活作用。我们建议用药物化学的方法来
优化这一系列的分子,以产生具有全细胞活性的有效和PfPKG选择性化合物,
在小鼠体内试验的可接受的药物特性。
项目成果
期刊论文数量(0)
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Purnima Bhanot其他文献
Purnima Bhanot的其他文献
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{{ truncateString('Purnima Bhanot', 18)}}的其他基金
Development of inhibitors of P. falciparum cGMP dependent protein kinase (PfPKG) for malaria chemoprevention
开发用于疟疾化学预防的恶性疟原虫 cGMP 依赖性蛋白激酶 (PfPKG) 抑制剂
- 批准号:
9751740 - 财政年份:2017
- 资助金额:
$ 72.12万 - 项目类别:
Identification of the target of a compound that inhibits plasmodium sporozoites
抑制疟原虫子孢子的化合物靶标的鉴定
- 批准号:
8384110 - 财政年份:2012
- 资助金额:
$ 72.12万 - 项目类别:
Identification of the target of a compound that inhibits plasmodium sporozoites
抑制疟原虫子孢子的化合物靶标的鉴定
- 批准号:
8716838 - 财政年份:2012
- 资助金额:
$ 72.12万 - 项目类别:
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