Mechanistic studies of gamma-glutamyl transpeptidase inhibition: A novel approach to modulating serum levels of cysteine
γ-谷氨酰转肽酶抑制的机制研究:调节半胱氨酸血清水平的新方法
基本信息
- 批准号:10004119
- 负责人:
- 金额:$ 31.75万
- 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:2018-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAffinityAnimalsBasic ScienceBiological AssayBiological ModelsBiologyCell Culture TechniquesCellsChemicalsCrystallizationCysteineCystineD GlutamateDataDependenceDevelopmentDiseaseDrug DesignEnzyme InhibitionEnzyme KineticsEnzymesEssential Amino AcidsExcretory functionFoundationsFutureGamma-glutamyl transferaseGenerationsGlutamatesGlutathioneGoalsHomeostasisHourHumanIn VitroIsomerismKidneyKineticsKnockout MiceKnowledgeLeadLong-Term EffectsLung NeoplasmsMalignant NeoplasmsMetabolicMissionModificationMolecularMolecular ProbesMonitorMusNitrogenOncogenesOxidation-ReductionOxidesPathway interactionsPharmaceutical ChemistryPositioning AttributeProcessPropertyProtein BiosynthesisProtocols documentationPublic HealthReactive Oxygen SpeciesResearchResearch PersonnelResistanceRoleSeriesSerumSpecificityStructureSupplementationTextUnited States National Institutes of HealthUrineanalogbasecancer therapychemotherapycomparative efficacydesignenzyme mechanismexperimental studyin vivoinhibitor/antagonistinsightmelanomamolecular modelingmouse modelnovelnovel strategiesnovel therapeuticspressurepreventresponsesmall moleculesmall molecule inhibitorstructural biologytooltumortumor growthtumor progressionuptake
项目摘要
Gamma-glutamyl transpeptidase (GGT) is essential for cysteine homeostasis in vivo. There are no potent,
specific non-toxic inhibitors of GGT that can be used as molecular probes in studies of the disruption of cysteine
homeostasis. Such studies are needed to increase our understanding of many disease processes including
cancer. Tumors have an enhanced requirement for cysteine. The long term goal of this research is to study the
mechanisms by which cysteine availability impacts tumor progression and response to therapy. The central
hypothesis in this proposal is that potent, non-toxic, highly specific inhibitors of GGT1 administered systemically
will deplete the serum of cysteine. The objectives of this application are to investigate the catalytic mechanism
of GGT, using insights from kinetic and structural studies to develop two mechanistically distinct classes of GGT
inhibitors and provide in vivo proof-of-biology that small molecule inhibitors of GGT1 can be used to modulate
serum cysteine levels. These objective will be met by studies outlined in three specific aims. In Aim I structural
studies of inhibitor-bound hGGT1 and molecular modeling will be used to design new sets of analogs of a high
potency competitive inhibitor of hGGT1. The new compounds will be synthesized and analyzed for potency and
specificity as inhibitors of hGGT1 in kinetic assays and cell culture model systems. The most potent inhibitors
will be co-crystallized with hGGT1 and the structures solved. We will use an iterative strategy to optimize the
potency and specificity of the analogs. Using the strategy outlined in Aim I, in Aim II we will undertake
development of a novel class of uncompetitive inhibitors that we have identified of hGGT1. Based on our
preliminary data, we hypothesize that studying the interaction of these compounds with the enzyme will provide
additional knowledge of the catalytic activity of GGT. This knowledge will be applied to the studies in both Aims
I and II. Aim III will focus on proof-of-biology studies in mice. The mice will be treated with the most potent and
specific compounds from each of the two aims. Cysteine concentrations in the serum will be monitored following
administration of the compound. These experiments will be compare the efficacy of competitive and
uncompetitive inhibitors in vivo. These studies will be undertaken by an established team of investigators with
expertise in structural biology, molecular modeling, medicinal chemistry, enzyme kinetics, and use of inhibitors
as probes in in vitro and in vivo studies. We are well positioned for these studies as the first and only group to
crystallize and solve the structure of any eukaryotic GGT. Successful completion of the proposed studies will
provide valuable molecular probes for future mechanistic studies of the effect of GGT inhibition and modulation
of serum cysteine on tumors.
γ-谷氨酰转肽酶(GGT)是体内半胱氨酸稳态所必需的。没有强大的,
特异性无毒GGT抑制剂,可用作半胱氨酸破坏研究中的分子探针
体内平衡需要这些研究来增加我们对许多疾病过程的理解,包括
癌肿瘤对半胱氨酸的需求增加。本研究的长期目标是研究
半胱氨酸利用率影响肿瘤进展和对治疗反应的机制。中央
该建议中的假设是,全身施用的有效的、无毒的、高度特异性的GGT 1抑制剂
会耗尽血清中的半胱氨酸本申请的目的是研究催化机理
的GGT,利用动力学和结构研究的见解,开发两种不同类型的GGT
抑制剂,并提供了体内生物学证据,即GGT 1的小分子抑制剂可用于调节
血清半胱氨酸水平。这些目标将通过三个具体目标概述的研究来实现。在Aim I结构中
结合hGGT 1的研究和分子建模将用于设计一组新的类似物,
hGGT 1的效力竞争性抑制剂。新化合物将被合成并分析其效力,
在动力学测定和细胞培养模型系统中作为hGGT 1抑制剂的特异性。最有效的抑制剂
将与hGGT 1共结晶,结构得到解决。我们将使用迭代策略来优化
类似物的效力和特异性。利用目标一概述的战略,在目标二中,我们将
开发了一类新的非竞争性抑制剂,我们已经确定了hGGT 1。基于我们
根据初步数据,我们假设研究这些化合物与酶的相互作用将提供
GGT催化活性的额外知识。这些知识将应用于两个目标的研究
一期及第二期Aim III将专注于小鼠的生物学验证研究。小鼠将接受最有效的治疗,
这两个目标中的每一个的特定化合物。将在以下时间监测血清中的半胱氨酸浓度:
化合物的施用。这些实验将比较竞争性和
体内的非竞争性抑制剂。这些研究将由一个既定的研究者团队进行,
结构生物学、分子建模、药物化学、酶动力学和抑制剂使用方面的专业知识
作为体内和体外研究的探针。作为第一个也是唯一一个
结晶并解析真核GGT的结构成功完成拟议的研究将
为进一步研究GGT的抑制和调节作用机制提供了有价值的分子探针
血清半胱氨酸对肿瘤的影响
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.
2-氨基-4-硼丁酸(ABBA)的新型类似物的设计和评估,作为人γ-谷氨酰基肽酶的抑制剂。
- DOI:10.1016/j.bmc.2022.116986
- 发表时间:2022-11-01
- 期刊:
- 影响因子:3.5
- 作者:Nguyen, Luong;Schultz, Daniel C.;Terzyan, Simon S.;Rezaei, Mohammad;Songb, Jinhua;Li, Chenglong;You, Youngjae;Hanigan, Marie H.
- 通讯作者:Hanigan, Marie H.
Crystal structures of glutathione- and inhibitor-bound human GGT1: critical interactions within the cysteinylglycine binding site.
- DOI:10.1074/jbc.ra120.016265
- 发表时间:2021-01
- 期刊:
- 影响因子:0
- 作者:Terzyan SS;Nguyen LT;Burgett AWG;Heroux A;Smith CA;You Y;Hanigan MH
- 通讯作者:Hanigan MH
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MARIE H HANIGAN其他文献
MARIE H HANIGAN的其他文献
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{{ truncateString('MARIE H HANIGAN', 18)}}的其他基金
Structural characterization of gamma-glutamyl transferase enzymes
γ-谷氨酰转移酶的结构表征
- 批准号:
8666007 - 财政年份:2014
- 资助金额:
$ 31.75万 - 项目类别:
Structural characterization of gamma-glutamyl transferase enzymes
γ-谷氨酰转移酶的结构表征
- 批准号:
8518427 - 财政年份:2013
- 资助金额:
$ 31.75万 - 项目类别:
Structural characterization of gamma-glutamyl transferase enzymes
γ-谷氨酰转移酶的结构表征
- 批准号:
8465593 - 财政年份:2012
- 资助金额:
$ 31.75万 - 项目类别:
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