Novel Small Molecule Agonists of Integrin CD11b/CD18 as Anti-Inflammatory Agents

描述（由申请人提供）：白细胞浸润会加剧腹膜炎、肾缺血再灌注损伤，这是急性肾衰竭和其他急性炎症病症的主要原因。同样，白细胞浸润是狼疮性肾炎慢性炎症过程中的关键启动步骤，导致肾功能进行性恶化以及各种其他自身免疫性疾病。实验模型研究表明，调节白细胞募集是有益的，并且可以降低动物中此类疾病的严重程度或发病机制。 白细胞 2 整合素 CD11b/CD18（又名 Mac-1、aMb2）对于这些细胞的各种功能至关重要。使用抗体和配体模拟物阻断 CD11b/CD18 与其配体结合的传统方法（抗粘附疗法）在动物模型中显示白细胞浸润显着减少，但在多项临床试验中未能治疗炎症/自身免疫性疾病。在这里，我们提出了一种通过使用小分子激活而不是阻断整合素 CD11b/CD18 来治疗炎症性疾病的创新方法。我们提出，用小分子激活 CD11b/CD18 将阻止白细胞迁移到炎症部位，这一前提是基于 15 年前发表的文献，该文献也为这一假设提供了体内支持。然而，我们的方法是新颖的，其特点是我们能够使用新型 CD11b/CD18 小分子激动剂激活整合素，这些激动剂可以全身递送，并且在未来易于修改和改进。该提案中提出的初步数据表明，整合素特异性小分子介导的 CD11b/CD18 激活可减少白细胞浸润和炎症，并且可以成为治疗多种炎症和自身免疫性疾病的有效且药理学上有用的方法。我们还意外地发现，这些化合物对 CD11b/CD18 的激活会抑制促炎细胞因子和其他因子的分泌，尽管目前尚不清楚调节这种抗炎作用的细胞内途径的性质。这表明新型 CD11b/CD18 激动剂代表了一类新型抗炎剂，可通过减少白细胞迁移和直接抑制白细胞促炎功能来减少炎症损伤。该提案的总体目标是在体外和体内充分表征我们新发现的 CD11b/CD18 激动剂功能的分子和细胞基础，并探索其体内治疗潜力。我们提出的研究将为未来开发治疗上有用的抗炎药物和策略开辟新途径，包括导致肾功能进行性恶化和急性肾衰竭的抗炎药物和策略。

DESCRIPTION (provided by applicant): Infiltration of leukocytes potentiates peritonitis, renal ischemia-reperfusion injury, a major cause of acute renal failure, and other acute inflammatory conditions. Likewise, leukocyte infiltration is a key initiating step during chronic inflammation in lupus nephritis, resulting in progressive deterioration of kidney function, and in various other autoimmune diseases. Studies in experimental models have shown that modulating leukocyte recruitment is beneficial and decreases the severity or the pathogenesis of such diseases in animals. The leukocytic 2 integrin CD11b/CD18 (a.k.a. Mac-1, aMb2) is central to various functions of these cells. Conventional approaches using antibodies and ligand mimics to block binding of CD11b/CD18 to its ligands (anti-adhesion therapy), which showed marked reduction in leukocyte infiltration in animal models, failed in treating inflammatory/autoimmune diseases in several clinical trials. Here, we propose an innovative approach for treating inflammatory disease by activating, not blocking, integrin CD11b/CD18 using small molecules. We propose that CD11b/CD18 activation with small molecules would prevent leukocyte migration to the site of inflammation, a premise that is based on published literature going back 15 years that also provides in vivo support for this hypothesis. However, our approach is novel and is distinguished by our ability to activate integrins using novel small molecule agonists of CD11b/CD18 that can be systemically delivered and are easy to modify and improve upon in the future. The preliminary data presented in this proposal suggests that integrin-specific small molecule mediated activation of CD11b/CD18 reduces leukocyte infiltration and inflammation and can be an effective, pharamacologically useful methodology to treat a variety of inflammatory and autoimmune diseases. We have also made an unexpected discovery that activation of CD11b/CD18 by these compounds suppresses secretion of pro-inflammatory cytokines and other factors, although the nature of intracellular pathways modulating this anti-inflammatory effect is currently not known. This suggests that the novel CD11b/CD18 agonists represent a new class of anti-inflammatory agents that reduce inflammatory injury by decreasing leukocyte migration and by directly suppressing the proinflammatory function of leukocytes. The overall goal of this proposal is to fully characterize the molecular and the cellular basis for the function of our newly discovered CD11b/CD18 agonists in vitro and in vivo and to explore their therapeutic potential in vivo. Our proposed studies would open up new avenues for the development of therapeutically useful anti-inflammatory agents and strategies in the future, including ones that lead to progressive deterioration of kidney function and acute renal failure.