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

描述(申请人提供)：白细胞的渗透会加重腹膜炎、肾缺血-再灌注损伤，这是急性肾功能衰竭的主要原因，以及其他急性炎症情况。同样，在狼疮性肾炎和其他各种自身免疫性疾病中，白细胞浸润是慢性炎症的关键启动步骤，导致肾功能的进行性恶化。在实验模型中的研究表明，调节白细胞募集是有益的，并降低了动物此类疾病的严重性或发病机制。白细胞2整合素CD11b/CD18(又名MAC-1、aMb2)是这些细胞的各种功能的中心。传统的方法使用抗体和配体模拟来阻断CD11b/CD18与其配体的结合(抗黏附治疗)，在动物模型中显示白细胞渗透显著减少，在几个临床试验中未能治疗炎症性/自身免疫性疾病。在这里，我们提出了一种利用小分子激活整合素CD11b/CD18而不是阻断整合素CD11b/CD18来治疗炎症性疾病的创新方法。我们认为，小分子激活CD11b/CD18可以防止白细胞迁移到炎症部位，这一前提基于15年前发表的文献，也为这一假说提供了体内支持。然而，我们的方法是新颖的，其特点是我们能够使用新的CD11b/CD18小分子激动剂激活整合素，这些小分子激动剂可以系统地递送，并且在未来很容易修改和改进。本研究提供的初步数据表明，整合素特异性小分子介导的CD11b/CD18激活可以减少白细胞的渗透和炎症，可以成为一种有效的、药理上有用的方法来治疗各种炎症性和自身免疫性疾病。我们还有一个意想不到的发现，这些化合物激活CD11b/CD18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的抗炎药，通过减少白细胞的迁移和直接抑制白细胞的促炎功能来减轻炎症损伤。这项建议的总体目标是充分描述我们新发现的CD11b/CD18激动剂在体外和体内发挥作用的分子和细胞基础，并探索它们在体内的治疗潜力。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功能衰竭的抗炎药和策略。

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.