Characterization of activity and mechanism of novel fungicidal anti-cryptococcal molecules
新型杀菌抗隐球菌分子的活性和机制表征
基本信息
- 批准号:9141008
- 负责人:
- 金额:$ 23.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-01 至 2018-02-28
- 项目状态:已结题
- 来源:
- 关键词:2 year oldAIDS/HIV problemAddressAffectAfrica South of the SaharaAlgorithmsAlternative TherapiesAmphotericin BAnimal ModelAnti-Retroviral AgentsAntifungal AgentsBenzimidazolesBiological AssayBlood - brain barrier anatomyCell WallCellsChemistryClinicalCollectionCryptococcal MeningitisCryptococcus neoformansCryptococcus neoformans infectionDataDeath RateDevelopmentDrug CombinationsEpidemiologic StudiesEvaluationFluconazoleFlucytosineFundingGoalsGoldHIVHumanHuman Cell LineIn VitroIndustrial fungicideInstitutesLaboratoriesLethal Dose 50LibrariesLifeMedicalMeningoencephalitisMolecular BankMolecular ProbesMolecular TargetNatureNew AgentsOpportunistic InfectionsOutcomePathway interactionsPatientsPersonsPharmaceutical ChemistryPharmaceutical PreparationsPrevalenceProcessRegimenResearch InfrastructureResourcesSignal TransductionSqualene SynthetaseStagingStructureStructure-Activity RelationshipTestingThioureaToxic effectTuberculosisUnited States National Institutes of HealthValidationadenylate kinasebasebenzimidazoleburden of illnesschemical geneticsdesigndrug candidateeffective therapygenetic approachgenomic profilesglobal healthhigh throughput screeningimprovedinhibitor/antagonistkillingsmutantnovelnovel therapeuticspathogenpre-clinicalprogramspublic health relevanceresearch studyscaffoldscreeningsmall molecule
项目摘要
DESCRIPTION (provided by applicant): Cryptococcal meningitis is one of the most important opportunistic infections affecting people living with HIV/AIDS. Recent epidemiologic studies indicate that approximately 1 million new cases occur each year and over 700,000 people die each year; in sub-Saharan Africa, more HIV patients die of cryptococcal meningitis each year than tuberculosis. The gold standard therapy for cryptococcosis is amphotericin B combined with 5-flucytosine. Although this regimen is easily administered in resource-rich regions of the world, it is not available in many resource-limited regions with the highest burden of disease. In these regions, fluconazole, a less effective, fungistatic agent, is used because it is readily available, safe, and administered orally. Unfortunately, patients treated with FLU have much higher death rates; this has been attributed to the fungistatic activity of FLU. Thus, new therapies for cryptococcosis are urgently needed and this is the long-term goal of our project. Because molecules with fungicidal activity are clinically superior to fungistatic drugs, we have developed a high throughput screening assay that directly identifies molecules with fungicidal activity toward C. neoformans. We have screened two distinct libraries with the assay: 1) a 350,000 compound library through an NIH-funded Molecular Probes and Library Screening Network project and 2) a focused set of 700 molecules from Merck Laboratories collection of anti-candidal molecules. The former screen was designed to identify a molecule with activity against cell wall related processes in C. neoformans: a novel benzimidazole thiourea scaffold with low human toxicity and good anti-cryptococcal activity emerged from this screen. We will identify its mechanism of action in Aim 1 to set the stage for subsequent optimization of its anti-cryptococcal activity. From the Merck Library, we have identified 22 molecules with fungicidal activity against C. neoformans at concentrations ≤ 2 µg/mL. We will complete the secondary screening of the set of Merck library hits in Aim 2 and identify the mechanism of action for a tota of four high priority scaffolds. Initial evaluation indicates that a set of squalene synthase inhibitors are among the hits. We will test that hypothesis and identify the target of three high priority scaffolds from the remaining hits. The mechanistic information that emerges from this exploratory project will be used as a basis for a subsequent application to optimize the anti-cryptococcal activity of the scaffolds.
描述(由申请人提供):隐球菌性脑膜炎是影响艾滋病毒/艾滋病患者的最重要的机会性感染之一,最近的流行病学研究表明,撒哈拉以南地区每年约有 100 万新病例,每年有超过 70 万人死亡;在非洲,每年死于隐球菌性脑膜炎的艾滋病毒患者比死于结核病的患者还要多。隐球菌病的金标准疗法是两性霉素 B 联合治疗。尽管这种疗法在世界资源丰富的地区很容易使用,但在许多疾病负担最高的资源有限的地区却无法使用氟康唑,这是一种效果较差的抑真菌剂。不幸的是,接受 FLU 治疗的患者的死亡率要高得多;这归因于 FLU 的抑制真菌活性,因此迫切需要新的隐球菌病治疗方法。由于具有杀真菌活性的分子在临床上优于抑真菌药物,因此我们开发了一种高通量筛选方法,可以直接鉴定对新型隐球菌具有杀真菌活性的分子。 :1) 通过 NIH 资助的分子探针和库筛选网络项目建立了 350,000 个化合物库,2) 来自默克实验室收集的 700 个重点分子前一个筛选旨在鉴定对新型念珠菌中的细胞壁相关过程具有活性的分子:我们将鉴定其具有低人体毒性和良好的抗隐球菌活性的新型苯并咪唑硫脲支架。目标 1 中的作用机制为其抗隐球菌活性的后续优化奠定了基础 从默克图书馆中,我们鉴定了 22 种在一定浓度下对新型隐球菌具有杀菌活性的分子。 ≤ 2 µg/mL。我们将完成目标 2 中默克文库命中的二次筛选,并确定总共四种高优先级支架的作用机制,初步评估表明一组角鲨烯合酶抑制剂属于其中。我们将测试该假设并从剩余的命中中确定三个高优先级支架的目标。从该探索性项目中产生的机制信息将用作后续应用程序优化的基础。支架的抗隐球菌活性。
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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Damian J Krysan其他文献
Damian J Krysan的其他文献
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10241688 - 财政年份:2021
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10646327 - 财政年份:2021
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Discovery and optimization of antifungal acetyl CoA synthetase inhibitors
抗真菌乙酰辅酶A合成酶抑制剂的发现和优化
- 批准号:
10448463 - 财政年份:2021
- 资助金额:
$ 23.03万 - 项目类别:
Hit-to-lead optimization of broad spectrum antifungal phenothiazines
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10311751 - 财政年份:2021
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Genetic and mechanistic analysis of carbon dioxide tolerance in Cryptococcus pathogenesis
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- 批准号:
10335205 - 财政年份:2020
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Genetic and mechanistic analysis of carbon dioxide tolerance in Cryptococcus pathogenesis
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- 批准号:
10548836 - 财政年份:2020
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Systematic in vitro and in vivo genetic analysis of C.albicans protein kinases
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