Structure and function of integrins in the kidney

肾脏整合素的结构和功能

基本信息

批准号：
9354435
负责人：
M. AMIN ARNAOUT
金额：
$ 23.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9354435
关键词：
Accounting Acute Address Adhesions Adult Affinity Agonist Animal Model Antibodies Atherosclerosis Autoimmune Diseases Autoimmune Process Autoimmunity Binding Binding Proteins Binding Sites Biochemical Biological Assay Biology Biophysics Blood Blood Platelets Cell Adhesion Cell membrane Cell surface Cells Cessation of life Chemicals Chronic Clinical Trials Communication Complex Complications of Diabetes Mellitus Crystallization Cyclic Peptides Cytoplasmic Tail Data Development Diabetic Nephropathy Disease Drug Design Epitopes Evaluation Extracellular Matrix F-Actin FDA approved Family Family suidae Fibrosis Funding Generations Head Hemorrhage High Fat Diet Human Immune Impairment Inflammatory Integrin Binding Integrin alpha Chains Integrin alphaVbeta3 Integrin beta3 Integrins Ions Kidney Kidney Diseases Leg Length Life Ligand Binding Ligands Mediating Medical Metals Molecular Conformation Monoclonal Antibodies Myocardial Infarction Oral Organism Pathogenesis Pathogenicity Pathology Patients Pattern Pharmaceutical Preparations Physiological Process Publishing RGD (sequence)Regulation Risk Role Series Signal Transduction Signaling Protein Site Stimulus Structure Structure-Activity Relationship Systemic Scleroderma Therapeutic Thrombocytopenia Thrombosis Travel Tumor Angiogenesis abciximab acute coronary syndrome adhesion receptor adverse outcome base chemokine clinical efficacy design diabetic drug development eptifibatide extracellular mimetics mouse model novel overexpression peptidomimetics premature prevent public health relevance receptor small molecule synthetic drug therapeutic target tirofiban tumor growth

项目摘要

DESCRIPTION (provided by applicant): In multicellular organisms, a family of tightly regulated cell adhesion receptors called integrins mediates communication among cells and between cells and their extracellular matrices. Impaired regulation of integrins leads to many pathologies, which in the adult kidney include inflammatory, autoimmune and thrombotic disorders, making integrins important therapeutic targets. Indeed FDA-approved peptidomimetics, synthetic small molecules and monoclonal antibodies (mAbs) are being used to treat thrombotic and autoimmune diseases, and more recently, mAbs targeting αVβ3 have been shown to prevent atherosclerosis, diabetic nephropathy and systemic sclerosis in animal models. The anti-integrin peptidomimetics and synthetic small molecule drugs in current use are patterned after the prototypical integrin binding Arg-Gly-Aps motif in ligands. Their parenteral use has caused serious adverse outcomes in treated patients, and clinical trials using these ligand-mimetics as oral drugs to prevent thrombosis have failed due to unexpected patient death of paradoxical thrombosis. Subsequent biochemical and structural studies showed that these drugs act as partial agonists, i.e. they induce the conformational changes in the integrin produced by binding of physiologic macromolecular ligands. This partial agonism has contributed to the unexpected adverse outcomes seen in treated patients. Hence the need for a better understanding of structure- activity relationships in these receptors and for development of "pure" antagonists that lack the partial agonism of the ligand-mimetic compounds in current use. Our recently published studies generated during the current funding period identified an RGD-based "pure" antagonist and revealed the atomic basis for its unexpected mechanism of action. These studies, in addition to new preliminary data, provide a novel path for synthesis of anti-integrin drugs that lack partial agonism, and a basis for understanding structure-function relationships in integrins in more details. Capitalizing on these exciting new developments is the subject of this competing renewal application.

描述（由申请人提供）：在多细胞生物体中，称为整合素的严格调节的细胞粘附受体家族介导细胞之间以及细胞与其细胞外基质之间的通讯。整合素调节受损会导致许多病变，在成人肾脏中包括炎症、事实上，整合素是 FDA 批准的肽模拟物、合成小分子和单克隆抗体 (mAb) 的重要治疗靶点。用于治疗血栓形成和自身免疫性疾病，最近，针对 αVβ3 的单克隆抗体已在动物模型中被证明可以预防动脉粥样硬化、糖尿病肾病和系统性硬化症，目前使用的抗整合素肽模拟物和合成小分子药物都是仿照原型设计的。配体中整合素结合 Arg-Gly-Aps 基序它们的肠外使用已在治疗的患者中造成严重的不良后果，并且使用这些药物的临床试验。配体模拟物作为预防血栓形成的口服药物失败了，因为患者因矛盾血栓形成而意外死亡。随后的生化和结构研究表明，这些药物起到部分激动剂的作用，即它们通过生理大分子配体的结合诱导整合素的构象变化。这种部分激动导致了治疗患者出现意想不到的不良后果，因此需要更好地了解这些受体的结构-活性关系，并开发出“纯”拮抗剂。缺乏目前使用的配体模拟化合物的部分激动作用，我们最近发表的研究在当前资助期间确定了一种基于 RGD 的“纯”拮抗剂，并揭示了其意想不到的作用机制的原子基础。根据新的初步数据，提供了一种合成缺乏部分激动作用的抗整合素药物的新途径，并为更详细地了解整合素的结构-功能关系奠定了基础，利用这些令人兴奋的新进展是本次竞争性更新申请的主题。。