Structure and function of integrins in the kidney

描述（由申请人提供）：在多细胞生物中，一个被称为整合素的严格调控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信。整合素的调节受损导致许多病理，其中在成人肾脏中包括炎症、自身免疫和血栓性疾病，使整合素成为重要的治疗靶点。事实上，fda批准的肽模拟物、合成小分子和单克隆抗体（mab）正被用于治疗血栓性和自身免疫性疾病，最近，靶向αVβ3的mab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类药物和合成小分子药物都是根据整合素结合Arg-Gly-Aps基序的配体原型设计的。在接受治疗的患者中，它们的肠外使用已经造成了严重的不良后果，并且使用这些配体模拟物作为口服药物来预防血栓形成的临床试验由于患者意外死亡而失败。随后的生化和结构研究表明，这些药物起到部分激动剂的作用，即它们诱导生理性大分子配体结合产生的整合素的构象变化。这种部分激动作用导致治疗患者出现意想不到的不良结果。因此，有必要更好地了解这些受体的结构-活性关系，并开发“纯”拮抗剂

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.