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

描述（由申请方提供）：白细胞浸润可加重腹膜炎、肾缺血-再灌注损伤（急性肾衰竭的主要原因）和其他急性炎症性疾病。同样，白细胞浸润是狼疮性肾炎慢性炎症过程中的关键起始步骤，导致肾功能进行性恶化，以及各种其他自身免疫性疾病。在实验模型中的研究表明，调节白细胞募集是有益的，并且降低了动物中此类疾病的严重程度或发病机制。 白细胞2整合素CD 11b/CD 18（a.k.a. Mac-1，aMb 2）是这些细胞的各种功能的核心。使用抗体和配体模拟物来阻断CD 11b/CD 18与其配体结合的常规方法（抗粘附疗法）在动物模型中显示出白细胞浸润的显著减少，但在几项临床试验中未能治疗炎性/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CD 11b/CD 18来治疗炎症性疾病的创新方法。我们提出，用小分子活化CD 11b/CD 18可以防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，并且通过我们使用新型CD 11b/CD 18的小分子激动剂激活整联蛋白的能力而与众不同，所述新型小分子激动剂可以全身递送并且在将来易于修饰和改进。该提案中提供的初步数据表明，整合素特异性小分子介导的CD 11b/CD 18活化可减少白细胞浸润和炎症，并且可以成为治疗各种炎症和自身免疫性疾病的有效的、药理学上有用的方法。我们还意外地发现，这些化合物对CD 11b/CD 18的激活抑制了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CD 11b/CD 18激动剂代表了一类新的抗炎剂，其通过减少白细胞迁移和直接抑制白细胞的促炎功能来减少炎性损伤。本提案的总体目标是充分表征我们新发现的CD 11b/CD 18激动剂在体外和体内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的途径，包括导致肾功能进行性恶化和急性肾衰竭的药物。 公共卫生相关性：提出的研究将使用各种人类肾脏疾病模型来测试我们新发现的化合物作为新型抗炎剂的有效性。我们相信，拟议的研究还将确定治疗人类炎症性疾病的新机制。

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. PUBLIC HEALTH RELEVANCE: The studies proposed will test the effectiveness of our newly discovered compounds as novel anti- inflammatory agents using various models of human kidney disease. We believe that the proposed studies will also identify novel mechanisms for treating inflammatory diseases in humans.