Drug development against Entamoeba histolytica
抗溶组织阿米巴药物开发
基本信息
- 批准号:9978458
- 负责人:
- 金额:$ 23.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-10 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse drug effectAlgorithmsAmoeba genusAnaerobic BacteriaAnimal ModelBasic ScienceBiologyBioterrorismCause of DeathCellsCessation of lifeCharacteristicsClinicalClinical DataClinical ResearchClinical TrialsColitisCollaborationsCystDataDeveloping CountriesDevelopmentDiseaseDrug Delivery SystemsDrug KineticsDrug ScreeningDrug TargetingDysenteryEntamoebaEntamoeba histolyticaExcisionExploratory/Developmental GrantFDA approvedFood ContaminationFoundationsFundingFutureGoalsGrantHepG2HumanInstitutesInvadedKineticsLactationLeadLettersLibrariesLife Cycle StagesLiver AbscessMedicalMethodsMetronidazoleMetronidazole resistanceMorbidity - disease rateNational Institute of Allergy and Infectious DiseaseNitroimidazolesOrganismOrphanOutcomeParasite resistanceParasitesPathogenesisPathogenicityPharmaceutical PreparationsPharmacotherapyPhaseRecording of previous eventsRecrudescencesRegimenResearchResistanceSafetyScientistSeriesSpeedTestingTherapeuticTimeTissuesToxic effectTranslationsTreatment ProtocolsWomanWorkbasecomparative efficacycontaminated watercostdata accessdesigndiarrheal diseasedrug developmentdrug discoveryexperiencehigh throughput screeninghuman pathogenimprovedin vivoin vivo evaluationmortalitymouse modelneglectnew therapeutic targetnovelnovel therapeuticspathogenpregnantscreeningstandard of caresuccesstransmission process
项目摘要
ABSTRACT
Entamoeba histolytica causes dysentery and liver abscesses with invasive disease in 50 million people
annually. Despite being an important human pathogen, this organism is poorly studied, has very limited
therapeutic options, and has no significant drug development pipeline. Thus, there is a critical need for new
drugs against this pathogenic ameba. We chose a compound screening approach using the ReFRAME library,
which was generated by Calibr and the Bill and Melinda Gates Foundation to have high-value hits with the vast
majority of compounds having been tested in humans. We have completed screening of ~11,000 compounds
against E. histolytica and identified 156 primary (~1.3%) hits. We subsequently performed confirmatory testing
and confirmed 50 hits with EC50 £15µM. By considering FDA approval status, clinical trial data, hepG2 cell
toxicity and potency against E. histolytica trophozoites, we identified 19 high-priority compounds for further
testing in this grant cycle. Of these 19 priority compounds, 9 have been FDA approved or have FDA orphan
designation and an additional 7 have been in late stage human clinical trials (Phase II or III); 14 have improved
efficacy compared to metronidazole. Thus, these 19 compounds are great options for a repurposing approach.
In this R21 grant, we will characterize these high value hits in the following two aims. In Aim 1, we will test
these compounds against Entamoeba cysts (encysting cells and mature cysts), metronidazole resistant
Entamoeba, and clinical isolates. We will also determine the kinetics of parasite killing with each compound
and the delay of parasite recrudescence after drug removal. Based on these results and analysis of
pharmacokinetic data on the compounds, in Aim 2, we will select ~2-5 select compounds to test in vivo
efficacy in a mouse model of Entamoeba colitis. Successful completion of this work will identify ~2 lead
compounds/series with activity against Entamoeba histolytica. Based on our experience with amebae,
significant drug development expertise at Stanford and UCSD, and a cadre of outstanding collaborators, we
are confident of a successful outcome.
摘要
溶组织内阿米巴导致5000万人感染痢疾和肝脓肿
每年。尽管是一种重要的人类病原体,但这种生物的研究很少,
治疗选择,并且没有重要的药物开发管道。因此,迫切需要新的
对抗这种致病性阿米巴的药物我们选择了使用ReFRAME库的化合物筛选方法,
这是由Calibr和比尔和梅林达盖茨基金会产生的,
大多数化合物已在人体中进行了测试。我们已经完成了约11,000种化合物的筛选
针对大肠histolytica,并确定了156个主要命中(~1.3%)。我们随后进行了确认性测试
并确认了50个命中,EC50为15 µ M。通过考虑FDA批准状态,临床试验数据,hepG2细胞
对大肠杆菌的毒力和效价。我们鉴定了19种高优先级化合物,
在这个周期里测试。在这19种优先化合物中,9种已获得FDA批准或具有FDA孤儿药
另有7个已进入晚期人体临床试验(II期或III期); 14个已改善
与甲硝哒唑相比。因此,这19种化合物是再利用方法的绝佳选择。
在这个R21补助金,我们将在以下两个目标中描述这些高价值的命中。在目标1中,我们将测试
这些化合物抗内阿米巴包囊(包囊细胞和成熟包囊),甲硝唑耐药
内阿米巴和临床分离株。我们还将确定每种化合物杀死寄生虫的动力学
以及药物去除后寄生虫复发的延迟。根据这些结果和分析,
在目标2中,我们将选择约2 - 5种选定化合物进行体内测试
内阿米巴结肠炎小鼠模型中的有效性。成功完成这项工作将确定约2个潜在客户
具有抗溶组织内阿米巴活性的化合物/系列。根据我们的经验,
在斯坦福大学和加州大学圣地亚哥分校的重要药物开发专业知识,以及优秀的合作者骨干,我们
有信心取得成功。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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UPINDER SINGH其他文献
UPINDER SINGH的其他文献
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{{ truncateString('UPINDER SINGH', 18)}}的其他基金
Extracellular vesicles, small RNAs, and intercellular communication in Entamoeba histolytica
溶组织内阿米巴的细胞外囊泡、小 RNA 和细胞间通讯
- 批准号:
9165169 - 财政年份:2016
- 资助金额:
$ 23.66万 - 项目类别:
Small RNA regulation of gene expression in Entamoeba
内阿米巴基因表达的小RNA调控
- 批准号:
9283327 - 财政年份:2016
- 资助金额:
$ 23.66万 - 项目类别:
Argonaute function in Entamoeba histolytica
Argonaute 在溶组织内阿米巴中的功能
- 批准号:
8889955 - 财政年份:2015
- 资助金额:
$ 23.66万 - 项目类别:
Transcription factor control of Entamoeba development
内阿米巴发育的转录因子控制
- 批准号:
8950071 - 财政年份:2015
- 资助金额:
$ 23.66万 - 项目类别:
Tools for regulated gene expression in Entamoeba invadens
内阿米巴入侵基因表达调控工具
- 批准号:
8998927 - 财政年份:2015
- 资助金额:
$ 23.66万 - 项目类别:
Development of Genetic Tools in Entamoeba histolytica
溶组织内阿米巴遗传工具的开发
- 批准号:
8391038 - 财政年份:2012
- 资助金额:
$ 23.66万 - 项目类别:
Development of Genetic Tools in Entamoeba histolytica
溶组织内阿米巴遗传工具的开发
- 批准号:
8515932 - 财政年份:2012
- 资助金额:
$ 23.66万 - 项目类别:
Transcriptome analysis of Entamoeba development using RNA-sequencing
使用 RNA 测序对内阿米巴发育进行转录组分析
- 批准号:
8129282 - 财政年份:2011
- 资助金额:
$ 23.66万 - 项目类别:
Transcriptome analysis of Entamoeba development using RNA-sequencing
使用 RNA 测序对内阿米巴发育进行转录组分析
- 批准号:
8265835 - 财政年份:2011
- 资助金额:
$ 23.66万 - 项目类别:
Developing tools for genetic manipulation in Entamoeba invadens
开发内阿米巴入侵基因操作工具
- 批准号:
8018169 - 财政年份:2010
- 资助金额:
$ 23.66万 - 项目类别: