Structure and function of integrins in the kidney

描述(申请人提供)：在多细胞生物体中，一种被称为整合素的严格调控的细胞黏附受体家族调节细胞之间以及细胞与其细胞外基质之间的通讯。整合素的调节受损会导致许多病理改变，包括炎症、自身免疫和血栓形成障碍，使整合素成为重要的治疗靶点。事实上，FDA批准的肽类药物、合成小分子和单抗(MAbb)正被用于治疗血栓性和自身免疫性疾病，最近，针对αVβ3的mAbb已被证明可以在动物模型中预防动脉粥样硬化、糖尿病肾病和系统性硬化症。目前使用的抗整合素多肽类药物和合成小分子药物都是仿照典型的整合素结合配体上的Arg-Gly-APS基序。它们的非肠道应用在接受治疗的患者中造成了严重的不良后果，使用这些配体模拟物作为口服药物预防血栓形成的临床试验因患者意外死亡而失败。随后的生化和结构研究表明，这些药物作为部分激动剂，即它们诱导通过与生理大分子配体结合而产生的整合素的构象变化。这种部分激动感导致了在接受治疗的患者中看到的意想不到的不良结果。因此，有必要更好地了解这些受体中的结构-活性关系，并开发出可 缺乏目前使用的类似配体的化合物的部分激动性。我们最近发表的研究发现了一种基于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。除了新的初步数据外，这些研究还为合成缺乏部分激动剂的抗整合素药物提供了一条新的途径，并为更详细地了解整合素的结构与功能关系提供了基础。利用这些令人兴奋的新发展是这项竞争性续签申请的主题。

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.