Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
基本信息
- 批准号:10469477
- 负责人:
- 金额:$ 53.35万
- 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:2019-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdhesionsAffinityAgonistAgreementAmericanBindingBinding SitesBiological AvailabilityBlood PlateletsCardiologyCell membraneCessation of lifeCollaborationsComplexCryoelectron MicroscopyCrystallizationCrystallographyCytoplasmic TailDataDetergentsDevelopmentDrug DesignDrug TargetingEarly treatmentEuropeanEventExcisionFaceGuidelinesHemorrhageHemostatic functionHeterogeneityHospitalsImmuneImpairmentIntegral Membrane ProteinIntegrinsLegLengthLibrariesLifeLigand BindingLigandsLinkMeasuresMembraneMembrane PotentialsMethodologyModelingMolecular ConformationMonitorMyocardial InfarctionNatureNegative StainingPathologicPatientsPeptide SynthesisPeptidesPharmaceutical PreparationsPhasePlatelet aggregationPre-hospital settingPreparationPrimatesPrior TherapyProteinsPublishingReceptor ActivationRecombinantsRegulationReportingResolutionRiskRoleSignal TransductionSocietiesSolidStructureStructure-Activity RelationshipSurface Plasmon ResonanceTechnologyTestingTherapeuticThrombocytopeniaThrombosisTransmembrane DomainWaterX-Ray Crystallographyadverse outcomeantagonistattack victimbaseclinical efficacycoronary thrombusdesigneptifibatidehigh riskimprovedimproved outcomeinhibitorinsightinterdisciplinary approachmimeticsmouse modelnovelpercutaneous coronary interventionpreventreceptorresponsesmall moleculetherapeutic targetthree dimensional structuretomographytwo-dimensional
项目摘要
Abstract
Platelet αIIbβ3 is required for normal hemostasis, but is also a validated drug target because of its essential
role in pathologic thrombosis. αIIbβ3 is normally kept in an inactive bent conformation on circulating platelets,
but rapidly switches to an active (ligand-binding) conformation in response to inside-out signaling. The ligand-
occupied receptor then transmits outside-in signals via the αβ transmembrane (TM) and cytoplasmic domains
that initiate platelet adhesion, a response inadvertently produced by current orthosteric inhibitory drugs, which
has limited their clinical efficacy. The structural basis of bidirectional integrin signaling remains to be clarified.
One model suggests that the ligand-binding site directly faces the plasma membrane in the bent conformation,
with integrin genuextension required for access to ligand. However, the integrin ectodomain/TM tilt has not
been defined experimentally. Further, regulated αβ TM domain association in integrins is driven by the
ectodomain, which may explain some of the differences found in the reported NMR structures of the isolated
αIIbβ3 TM domains. In preliminary studies, we produce a low-resolution cryo-EM structure of full-length αIIbβ3
in an unexpected orientation relative to the membrane, the result of its complex in cis with a tetraspanner,
providing the first experimental definition of an integrin ectodomain/TM tilt, and novel insights into the
structural basis of αIIbβ3 activation. We also develop a water soluble, stable and high affinity orthosteric
inhibitor of αIIbβ3 that is not a partial agonist, and use it in a structure-guided approach to generate like
compounds. We propose to expand on these preliminary data in three specific aims, utilizing multidisciplinary
approaches that include electron cryomicroscopy, tomography, protein crystallography, structure-based drug
design, new peptide synthesis technology and novel murine models of thrombosis.
摘要
血小板αIIbβ3是正常止血所必需的,但也是有效的药物靶点,因为它是必不可少的
在病理性血栓形成中的作用。αIIbβ3通常保持在循环血小板上的非活性弯曲构象中,
但响应内向外信号,迅速转换为活性(配体结合)构象。配基-
然后,被占领的受体通过αβ跨膜(TM)和细胞质结构域传递由外向内的信号
这种反应是由目前的正构体抑制药物无意中产生的,它
限制了它们的临床疗效。双向整合素信号转导的结构基础尚不清楚。
一种模型认为,在弯曲构象中,配体结合位置直接面对质膜,
具有获得配体所需的整合素真延伸。然而,整合素的胞外结构域/TM倾斜并没有
是通过实验定义的。此外,整合素中受调控的αβTM结构域关联是由
胞外结构域,这可能解释了已报道的分离的核磁共振结构中的一些差异
αIIbβ3 TM域。在初步研究中,我们生产了全长αIIbβ3的低分辨率低温EM结构
在相对于膜的意想不到的方向上,其结果是它的顺式与四叶刀的复合体,
提供了第一个整合素胞外结构域/TM倾斜度的实验定义,并对
αIIbβ3激活的结构基础。我们还开发了一种水溶性、稳定性和高亲和力的正构体
不是部分激动剂的αIIbβ3的抑制剂,并在结构指导的方法中使用它来产生LIKE
化合物。我们建议在三个具体目标上扩展这些初步数据,利用多学科
方法包括电子冷冻显微镜、断层扫描、蛋白质结晶学、基于结构的药物
设计、新的肽合成技术和新的小鼠血栓形成模型。
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(2)
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M. AMIN ARNAOUT其他文献
M. AMIN ARNAOUT的其他文献
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{{ truncateString('M. AMIN ARNAOUT', 18)}}的其他基金
Targeting innate immunity for induction of robust renal allograft tolerance
针对先天免疫诱导强大的肾同种异体移植耐受
- 批准号:
10622050 - 财政年份:2023
- 资助金额:
$ 53.35万 - 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
- 批准号:
10425736 - 财政年份:2022
- 资助金额:
$ 53.35万 - 项目类别:
Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys
抗CD40和抗CD11b mAb107联合使用对食蟹猴猪肾异种移植物存活的影响
- 批准号:
10618872 - 财政年份:2022
- 资助金额:
$ 53.35万 - 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
- 批准号:
10251142 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Platelet alphaIIbbeta3 activation and its therapeutic targeting
血小板αIIbbeta3激活及其治疗靶向
- 批准号:
10004711 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Role of integrin CD11b in delayed graft function and allorejection
整合素 CD11b 在移植物功能延迟和同种异体排斥中的作用
- 批准号:
9809349 - 财政年份:2019
- 资助金额:
$ 53.35万 - 项目类别:
Structure and Function of Integrins in the Kidney
肾脏中整合素的结构和功能
- 批准号:
10375579 - 财政年份:2010
- 资助金额:
$ 53.35万 - 项目类别:
Structure and function of integrins in the kidney
肾脏整合素的结构和功能
- 批准号:
9354435 - 财政年份:2010
- 资助金额:
$ 53.35万 - 项目类别:
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