Novel Features of Integrin Antagonism Applied to Renal Dysfunction

 描述（由申请人提供）：整合素是一种异源二聚体细胞粘附受体，通过与细胞外基质（ECM）的严格调节的金属依赖性相互作用，调节细胞迁移、增殖、分化、基质沉积和重塑，在发育和成年肾脏中发挥重要作用。用目前的配体模拟药物阻断整联蛋白的尝试是令人失望的，因为通过这些药物连接整联蛋白使受体稳定在活性构象中，使其能够在信号传导中触发外部，如 与天然配体，导致矛盾的细胞粘附和死亡率。我最近测定了与大分子配体复合的α V β 3的晶体结构，所述大分子配体是根据其对该整联蛋白的高亲和性和选择性而选择的。出乎意料的是，新结构阐明了配体-整联蛋白相互作用的新特征，其中配体同时结合但阻断整联蛋白的由外向内信号传导。我在这个建议的目的是使用这个令人兴奋的结果进行结构活性研究，导致设计纯整联蛋白拮抗剂，并测试这些配体模拟物之一，在一个既定的小鼠模型蛋白尿的肾保护作用。

 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.