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（由应用提供）：在多细胞生物中，一个称为整联蛋白的严格调节细胞粘附受体家族介导细胞之间以及细胞及其细胞外胎盘之间的通信。整联蛋白的调节受损会导致许多病理，在成年肾脏中包括炎症，自身免疫和血栓性疾病，使整联蛋白使整联蛋白成为重要的治疗靶点。实际上，通过FDA批准的肽仪，合成的小分子和单克隆抗体（MAB）已被用来治疗血栓形成和自身免疫性疾病，而最近，针对αVβ3的MABS的MABS已被证明可预防动脉粥样硬化，糖尿病性肾病性和系统性粘液症。抗整合蛋白的肽仪和合成小分子药物在当前使用中是在配体中原型整合蛋白结合arg-gly-aps基序后图案化的。他们的父母使用引起了治疗患者的严重逆境结局，并且使用这些配体模仿药作为口服药物来预防血栓形成的临床试验由于意外的患者死亡矛盾的血栓形成而失败。随后的生化和结构研究表明，这些药物是部分激动剂，即它们诱导通过物理大分子配体的结合产生的整联蛋白的构象变化。这种部分档案造成了治疗患者中意外的不良结果。因此，需要更好地理解这些受体中的结构活动关系以及发展“纯”拮抗剂缺乏当前使用中配体模拟化合物的部分激动。我们最近在当前资金期间生成的研究确定了基于RGD的“纯”拮抗剂，并揭示了其意外作用机理的原子基础。这些研究除了新的初步数据外，还为缺乏部分激动剂的抗整合蛋白药物的合成提供了新的途径，以及在更多细节中理解整联蛋白中结构功能关系的基础。利用这些令人兴奋的新发展是此竞争续约应用程序的主题。