New tools for antimalarial target identification
抗疟靶点识别的新工具
基本信息
- 批准号:9898297
- 负责人:
- 金额:$ 14.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-22 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAmodiaquineAntimalarialsArtemisininsBindingBiological AssayCambodianCellsCharacteristicsChemicalsClinicalCollectionComputing MethodologiesDataDatabasesDevelopmentDockingDrug Metabolic DetoxicationEndocytosisErythrocytesExhibitsFalciparum MalariaGenesGrantHematinHemeHemoglobinInvestigationLaboratoriesLibrariesLiteratureMalariaMapsMeasurementMeasuresMefloquineMethodsModelingMolecularMulti-Drug ResistanceNew YorkParasitesPathway interactionsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhenotypePlasmodium falciparumPredispositionPrevalenceProcessProteinsProteolysisPublicationsPublishingRefractoryReportingResearchResistanceRoleSeriesSiteSolventsSouth AfricaTestingTrainingUnited States National Institutes of HealthUniversitiesValidationVillusWorkanalytical methodbenflumetoldesigndrug discoveryexperienceexperimental studyhemozoinhigh throughput screeningimprovedin silicoinhibitor/antagonistinsightkinetic modelliquid chromatography mass spectrometrymathematical modelmutantnoveloverexpressionpathogenplasmepsinpredictive modelingpyridinepyronaridineresistant Plasmodium falciparumscreeningsmall molecule librariessuccesstoolvirtual laboratoryvirtual screening
项目摘要
Target identification is a vital step in the drug discovery process and represents a substantial hurdle to further
development when large numbers of hit compounds are identified by high throughput phenotypic screening. This
problem is especially challenging in the case of antimalarial drug discovery because of the prevalence of
unconventional targets such as hemozoin, the formation of which is thought to be inhibited by nearly half the
clinical antimalarials and many experimental compounds. A key feature of the success of these drugs is that
hemozoin is derived from host hemoglobin and is therefore not mutable, thereby reducing the ability of P.
falciparum to acquire resistance. Prior studies have shown that target identification is complicated by the fact
that the ability to inhibit abiotic synthetic hemozoin (-hematin) formation is a necessary, but not sufficient
predictor of hemozoin inhibition in Plasmodium falciparum malaria parasites and conversely, decreased
hemozoin formation in the parasite is not itself confirmation of direct inhibition of hemozoin formation. We
hypothesize that direct measurement of increased unsequestered heme together with decreased hemozoin in
the intra-erythrocytic parasite is the most consistent method of identifying hemozoin inhibitors and that the latter
cause characteristic perturbations of the heme detoxification pathway that can be exploited in target
deconvolution. We further hypothesize that these inhibitors occupy a distinct region of chemical space that can
be mapped in silico. To achieve our objectives, the following specific aims are proposed: 1) Develop
generalizable methods to measure and detect hemozoin inhibition in Plasmodium falciparum; 2) Use in silico
methods to map hemozoin inhibition in chemical space; and 3) Develop a model of the full heme detoxification
pathway. To realize these aims, the research will be conducted as a collaborative and synergistic project between
Timothy Egan at the University of Cape Town (UCT), Katherine de Villiers at Stellenbosch University (SU), South
Africa and David Fidock at the Columbia University Medical Center (CUMC), New York, NY. Generalizable
analytical methods for measuring unsequestered heme will be developed at UCT and transferred to CUMC for
investigation of compound collections available at that site. A laboratory strain expected to exhibit universally
reduced susceptibility to hemozoin inhibitors will be generated at CUMC. In silico methods for mapping -hematin
inhibitors will be developed at SU and screening via molecular docking performed at UCT. Validation of these
methods will take place at UCT and SU. The input data for modeling the heme detoxification pathway will be
collected at UCT, while the mathematical model of this pathway will be developed at SU. Validation of the model
will be conducted at UCT and CUMC. We expect that this work will transform our ability to discern the role of
hemoglobin degradation and hemozoin synthesis in the mode of action of antimalarials, and provide vital tools
to identify novel inhibitors that are refractory to a rapid gain of resistance and can treat multidrug-resistant P.
falciparum malaria.
目标识别是药物发现过程中至关重要的一步,是进一步
当通过高通量表型筛选鉴定大量命中化合物时的发展。这
在抗疟疾药物发现的情况下,这一问题尤其具有挑战性,因为
非常规靶标,如血球蛋白,其形成被认为被认为抑制了近一半
临床抗疟疾药物和许多实验化合物。这些药物成功的一个关键特征是
血球蛋白来源于宿主血红蛋白,因此不是突变的,因此降低了P。
恶性疟原虫获得抵抗力。先前的研究表明,目标识别由于以下事实而复杂化
抑制非生物合成血球蛋白(-hematin)形成的能力是必要的,但不是充分的
恶性疟原虫中血球蛋白抑制的预测因子,反之亦然
寄生虫中的血球蛋白形成本身并不能证实直接抑制血球蛋白的形成。我们
假设直接测量增加的未隔离的血红素和减少的血球蛋白
红细胞内寄生虫是鉴定血球蛋白抑制物最一致的方法,而后者
引起血红素解毒途径的特征性扰动,可用于靶向
去卷积。我们进一步假设,这些抑制剂占据了一个不同的化学空间区域,可以
用硅胶绘制地图。为了实现我们的目标,我们提出了以下具体目标:1)发展
测量和检测恶性疟原虫中血球蛋白抑制的通用方法;2)在硅胶中的应用
方法绘制化学空间的血球蛋白抑制图;3)建立血红素完全解毒模型。
路径。为了实现这些目标,这项研究将作为一个合作和协同的项目在
开普敦大学(UCT)的蒂莫西·伊根(Timothy Egan),南部斯泰伦博什大学(StellenBosch University)的凯瑟琳·德·维利尔斯(Katherine De Villiers)
纽约哥伦比亚大学医学中心(CUMC)的非洲和大卫·菲多克。概括性
UCT将开发测量未隔离血红素的分析方法,并将其移交给CUMC用于
对该地点现有的化合物收藏品进行调查。一种预计将在全球范围内表现出的实验室菌株
CUMC将降低对血球蛋白抑制剂的敏感性。在电子计算机中定位-血红素的方法
抑制剂将在SU开发,并在UCT通过分子对接进行筛选。对这些信息进行验证
方法将在UCT和SU进行。用于模拟血红素解毒途径的输入数据将为
而这一途径的数学模型将在苏黎世大学建立。模型的验证
将在UCT和CUMC进行。我们期待这项工作将改变我们辨别
抗疟药作用模式中的血红蛋白降解和血球蛋白合成,并提供重要工具
寻找对快速增加的耐药性具有抵抗力并可治疗多重耐药的新型抑制剂。
恶性疟疾。
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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Timothy John Egan其他文献
Timothy John Egan的其他文献
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{{ truncateString('Timothy John Egan', 18)}}的其他基金
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