Fosinopril analogs for the treatment of human babesiosis
福辛普利类似物用于治疗人类巴贝虫病
基本信息
- 批准号:10396069
- 负责人:
- 金额:$ 72.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-21 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adverse eventAffectAngiotensin-Converting Enzyme InhibitorsAnimal ModelAntihypertensive AgentsAzithromycinBabesiaBabesia microtiBabesiosisBiochemicalBiological AssayBiological AvailabilityBlack-legged TickBlood TransfusionBorrelia microtiBortezomibCase StudyChemicalsClindamycinClinicalClinical TrialsCombined Modality TherapyCommunicable DiseasesDataDermacentorDevelopmentDipeptidyl PeptidasesDiseaseDoseDrug CombinationsDrug KineticsDrug usageErythrocytesEstersFDA approvedFailureFormulationFutureGeneticGenetic studyGoalsGrowthHumanHybridsIn VitroInfectionKnowledgeLibrariesLinkMalariaMass Spectrum AnalysisMusParasitesParentsPeptide HydrolasesPharmaceutical PreparationsPharmacodynamicsProdrugsPropertyProteasome InhibitorPyrimethamineQuinineRecrudescencesRegimenReportingResistanceRouteSafetySerumSpecificityStructureStructure-Activity RelationshipSystemTherapeuticTherapeutic IndexTicksTreatment FailureTreatment ProtocolsUnited Statesanalogatovaquonebasedesigndrug candidateeffective therapyefficacy studyesterasehuman modelin vitro testingin vivoinhibitormouse modelmulticatalytic endopeptidase complexmutantpathogenpeptidyl-dipeptidase Dcppre-clinicalrational designresearch clinical testingside effectsuccesstick-borne
项目摘要
Babesiosis is a malaria-like illness found worldwide and endemic in the United States. The disease is caused
by intraerythrocytic parasites of the genus Babesia. Babesia microti and Babesia duncani, which are
responsible for most cases reported in the United States, are transmitted to humans by Ixodes scapularis and
Dermacentor albipictus ticks, respectively, and can also be introduced by blood transfusion. The current
treatment for human babesiosis consists of combination therapies with atovaquone+azithromycin or
clindamycin+quinine. However, these drugs are associated with high rate of recrudescence, treatment failures
and adverse events. Furthermore, recent studies in mice infected with B. microti and in vitro with B. duncani
showed that these parasites are naturally tolerant to these drugs. These limitations emphasize the need for
more effective and safer therapies for treatment of human babesiosis. We have recently reported the
development of a continuous in vitro culture system for B. duncani in human red blood cells. Using this assay,
we screened a library of FDA-approved drugs and identified fosinopril (the prodrug of the dipeptidyl
carboxypeptidase ACE inhibitor fosinoprilat) as a potent antibabesial inhibitor. The compound was also
effective against both B. duncani and B. microti in mouse models of babesiosis at 10 mg/kg. Interestingly,
neither fosinoprilat nor other ACE inhibitors affected the growth of B. duncani in vitro. Equally interesting,
analysis of the structure of fosinopril and bortezomib (another potent inhibitor of B. duncani identified in the
chemical screen and a known proteasome inhibitor) revealed similarities between the two compounds.
Together these data suggest that the antibabesial activity of fosinopril could be due to inhibition of either an
ACE-like peptidase and/or a proteasome activity of Babesia parasites. The primary goals of this application
are to identify analogs of fosinopril with more potent antibabesial but no ACE activity, and to elucidate the
mechanism of action of these compounds in Babesia parasites. Building upon our preliminary data, we
propose the following three specific aims. In Aim 1, we will determine whether or not the prodrug form of
fosinopril is the active compound, and characterize the efficacy of fosinopril and newly synthesized analogs
against B. duncani and B. microti clinical and field isolates in vitro and examine the structure activity
relationship specific to these parasites. In Aim 2, we will characterize the in vivo efficacy of the most active
compounds alone or in combination with other drugs as a strategy for elimination of Babesia infections. In Aim
3, we will implement biochemical, mass spectrometry and genetic assays to elucidate the mode of action of
and possible mechanisms of Babesia resistance to fosinopril and its analogs. The success of the proposed
three aims will guide future clinical trials to create an ideal regimen for the treatment of human babesiosis with
no recrudescence.
巴贝斯虫病是一种类似疟疾的疾病,在世界范围内发现,在美国流行。疾病是由
项目成果
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CHOUKRI BEN MAMOUN其他文献
CHOUKRI BEN MAMOUN的其他文献
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{{ truncateString('CHOUKRI BEN MAMOUN', 18)}}的其他基金
Fosinopril analogs for the treatment of human babesiosis
福辛普利类似物用于治疗人类巴贝虫病
- 批准号:
10211812 - 财政年份:2021
- 资助金额:
$ 72.59万 - 项目类别:
Fosinopril analogs for the treatment of human babesiosis
福辛普利类似物用于治疗人类巴贝虫病
- 批准号:
10594970 - 财政年份:2021
- 资助金额:
$ 72.59万 - 项目类别:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
人类巴贝虫寄生虫的抗原发现和疫苗开发
- 批准号:
10386919 - 财政年份:2020
- 资助金额:
$ 72.59万 - 项目类别:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
人类巴贝虫寄生虫的抗原发现和疫苗开发
- 批准号:
10163799 - 财政年份:2020
- 资助金额:
$ 72.59万 - 项目类别:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
人类巴贝虫寄生虫的抗原发现和疫苗开发
- 批准号:
10609400 - 财政年份:2020
- 资助金额:
$ 72.59万 - 项目类别:
Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
用于疟疾治疗的 Kalihinol 支架的 Hit-to-Lead 开发
- 批准号:
9789813 - 财政年份:2018
- 资助金额:
$ 72.59万 - 项目类别:
Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
用于疟疾治疗的 Kalihinol 支架的 Hit-to-Lead 开发
- 批准号:
10228612 - 财政年份:2018
- 资助金额:
$ 72.59万 - 项目类别:
Development of endochin-like quinolones for babesiosis therapy
用于治疗巴贝虫病的类内啡肽喹诺酮类药物的开发
- 批准号:
9392521 - 财政年份:2016
- 资助金额:
$ 72.59万 - 项目类别:
Probing the natural genomic diversity of Babesia microti
探究田鼠巴贝虫的自然基因组多样性
- 批准号:
9064063 - 财政年份:2015
- 资助金额:
$ 72.59万 - 项目类别:
Development of novel therapeutics for Babesia microti infection
田鼠巴贝虫感染新疗法的开发
- 批准号:
8865547 - 财政年份:2014
- 资助金额:
$ 72.59万 - 项目类别:
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