Novel Features of Integrin Antagonism Applied to Renal Dysfunction

整合素拮抗剂治疗肾功能障碍的新特点

基本信息

批准号：
8914273
负责人：
Johannes Franciscus Van Agthoven
金额：
$ 16.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914273
关键词：
Actins Acute Adult Affect Affinity Agonist Animal Model Binding Cell Adhesion Cell membrane Cells Chronic Cilengitide Clinical Trials Complex Cytoskeleton Deposition Development Disease Extracellular Matrix Fibronectins Functional disorder Goals Immune In Vitro Inflammatory Integrin Binding Integrins Kidney Kidney Diseases Lead Libraries Ligands Ligation Metals Modeling Molecular Conformation Mus Organ Outcome Peptides Phage Display Pharmaceutical Preparations Play Proteinuria RGD (sequence)Randomized Regulation Renal function Role Scaffolding Protein Signal Transduction Structure Structure-Activity Relationship Testing Work adhesion receptor base cell behavior cell motility design in vivo migration mimetics mortality mouse model mutant novel podocyte premature protective effect public health relevance receptor screening small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Integrins are a/ß heterodimeric cell adhesion receptors that play essential roles in the developing and adult kidney, through tightly regulated metal-dependent interactions with the extracellular matrix (ECM) that modulate cell migration, proliferation, differentiation, matrix deposition and remodeling. Attempts to block integrins with current ligand-mimetic drugs, have been disappointing, as ligation of the integrin by these drugs stabilizes the receptor in the active conformation, enabling it to trigger outside in signaling, as with natural ligands, leading to paradoxical cell adhesion and mortality. I have recently determined the crystal structure of aVß3 in complex with a macromolecular ligand selected for its high affinity and selectivity for this integrin. Unexpectedly, the new structure elucidated novl features of ligand-integrin interactions in which the ligand simultaneously binds but blocks outside-in signaling of the integrin. My aims in this proposal are to use this exciting result to carry-out structure-activity studies leading to design of pure integrin antagonists, and test the renoprotective effect of one of these ligand-mimetics in an established murine model of proteinuria.

描述（由适用提供）：整联蛋白是通过与细胞外基质（ECM）紧密调节的金属依赖性相互作用，可调节细胞迁移，增殖，差异，差异，基质沉积和重建，在发育和成人肾脏中起着重要作用的A/ß异二聚体细胞粘附受体。试图通过当前的配体模拟药物阻断整联蛋白，令人失望，因为这些药物通过这些药物结扎的结合使接收器稳定在主动构象中，从而使其能够在信号传导中触发外部，因为带有天然配体，导致矛盾的细胞粘附和死亡率。我最近已经确定了Avß3在复合物中的晶体结构，其中大分子配体以其高亲和力和该整合素的选择性选择。出乎意料的是，新结构阐明了配体 - 整合素相互作用的NOVL特征，其中配体完全结合，但会阻止整联蛋白的外部信号传导。我在该提案中的目的是利用这种令人兴奋的结果来进行结构活性研究，从而导致纯整合素拮抗剂的设计，并在既定的蛋白尿模型中测试这些配体模拟物之一的肉体保护作用。