Identification of CYP5122A1 inhibitors as chemical probes for Leishmania biology
鉴定 CYP5122A1 抑制剂作为利什曼原虫生物学化学探针
基本信息
- 批准号:10061546
- 负责人:
- 金额:$ 47.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-21 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAfghanistanAllelesAnabolismAzolesBindingBiochemicalBiological AssayBiologyBiteCase StudyChemicalsCommunicable DiseasesComplexCountryCrystallizationCutaneous LeishmaniasisCytochrome P450DangerousnessDiseaseDrug TargetingEnzyme KineticsEnzymesErgosterolExcisionExhibitsFluorescenceFutureGene DeletionGene MutationGrowthHigh Pressure Liquid ChromatographyHumanHybridsHypersensitivityImageImpairmentInfectionIraqKetoconazoleKnock-outLaboratoriesLanosterolLeftLeishmaniaLeishmania donovaniLeishmaniasisLifeLigand BindingLigandsMalariaMedicalMetabolic BiotransformationMilitary PersonnelOrganOrganismOutcomeParasitesParasitic DiseasesPathogenicityPathway interactionsPharmaceutical PreparationsPhlebotominaeProdrugsProteinsPublic HealthReactionResistanceRoentgen RaysRoleRouteSkinSterolsStructural ModelsStructureTestingVaccinesVisceral Leishmaniasisassay developmentbasechemotherapycostcytotoxicitydrug discoveryeffective therapyhigh throughput screeninginhibitor/antagonistinnovationmortalitynew therapeutic targetnovelposaconazolescreeningside effect
项目摘要
Summary
Human leishmaniasis is a devastating infectious disease caused by protozoan parasites belonging to
the genus of Leishmania. The disease is found in more than 90 countries and responsible for an estimated 1-2
million new infections each year worldwide. Leishmaniasis is also common in returning U.S. military personnel
from Iraq and Afghanistan, with more than two thousand cases reported since 2001. Leishmania parasites
cause disfiguring skin sores (cutaneous leishmaniasis or CL) and life-threatening infection of vital internal
organs (visceral leishmaniasis or VL). VL (~20% of all leishmaniasis cases) is the most dangerous and fatal
form of the disease, with a mortality rate close to 100% if left untreated. It is the second most deadly parasitic
disease in the world (after malaria). Despite being a serious public health problem in many endemic regions,
there are no vaccines or preventative chemotherapies available for leishmaniasis control. Current
antileishmanial drugs have limited efficacy, serious side effects and high cost. Hence, there is a major unmet
medical need for safe and effective drugs against leishmaniasis. Leishmanial CYP5122A1 is a novel
cytochrome P450 (CYP) enzyme that is essential for the survival of L. donovani, a major causative agent for
VL. Independent and our own studies have led us to hypothesize that identification of selective CYP5122A1
inhibitors as chemical probes will allow elucidation of its important role in the ergosterol biosynthesis by
Leishmania. To test our hypothesis, three specific aims are proposed to answer three main questions: 1) How
do the biochemical roles of CYP5122A1 and CYP51 compare in the ergosterol biosynthesis pathway of
Leishmania? 2) Can selective CYP5122A1 inhibitors be identified and validated? and 3) Are arylimidamides
(AIAs) and/or AIA-azole hybrids potential chemical probes to help delineate biochemical roles of CYP5122A1
in Leishmania biology? Innovative experimental approaches will be employed in the proposed project, e.g., a
new HPLC-MS/MS-based sterol assay, fluorescence-based CYP5122A1 and CYP51 inhibition assays, and
cutting-edge high content imaging-based intracellular antileishmanial assays. If successful, our proposed
project to identify novel CYP5122A1 inhibitors will elucidate this protein’s role in Leishmania biology and
validate CYP5122A1 as a drug target. Such an outcome could have a major positive impact on long-term
leishmaniasis control around the globe.
总结
项目成果
期刊论文数量(0)
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Zhuo Michael Wang其他文献
Zhuo Michael Wang的其他文献
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{{ truncateString('Zhuo Michael Wang', 18)}}的其他基金
Identification of CYP5122A1 inhibitors as chemical probes for Leishmania biology
鉴定 CYP5122A1 抑制剂作为利什曼原虫生物学化学探针
- 批准号:
10297860 - 财政年份:2018
- 资助金额:
$ 47.82万 - 项目类别:
Label-free quantitative proteomic methods for developmental pharmacology
用于发育药理学的无标记定量蛋白质组学方法
- 批准号:
9322598 - 财政年份:2016
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
- 批准号:
8507489 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
- 批准号:
8677602 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
- 批准号:
8138460 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
- 批准号:
8469669 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
- 批准号:
8304951 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
Human Cytochrome P450 4F Enzymes and Drug Interactions
人类细胞色素 P450 4F 酶和药物相互作用
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7984519 - 财政年份:2010
- 资助金额:
$ 47.82万 - 项目类别:
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