Development of small molecule inhibitors human altrenative pathway complement

描述（由申请人提供）：补体级联已经发展成为血液中对抗病原体的监测系统。然而，活化补体是一把双刃剑，有可能对宿主组织造成重大损害。因此，在正常情况下，补体活化是由一些调节蛋白严格控制的。这些调节蛋白的功能缺陷导致补体依赖性组织损伤和病理。几种人类疾病最近与失调的替代途径（AP）补体活性有关。其中，干性老年性黄斑变性（AMD）是一种常见的眼部疾病，影响着数百万美国老年人，可导致视力完全丧失。非典型溶血性尿毒症综合征（aHUS）是另一种以溶血、血栓性微血管病变和肾衰竭为特征的遗传性疾病。这两种疾病都与关键的AP补体调节蛋白因子H的突变有关，分别导致视网膜和内皮细胞的AP补体激活失控和炎症损伤。由于目前缺乏适当的治疗方法，这些情况很难治疗。我们假设开发有效的AP抑制剂将有助于控制补体激活，从而减少这些疾病的炎症和病理进展。在这个探索性研究项目中，我们将利用最近关键AP补体蛋白的结晶和结构测定，并利用这些知识来帮助基于计算机的药物设计。为此，我们建议采用高通量筛选和计算机辅助分子设计相结合的方法来鉴定和开发AP的小分子抑制剂，这些抑制剂可以进一步开发为AMD、aHUS和其他AP补体依赖性炎症疾病的治疗剂。我们将追求两个具体目标：我们将对已确定的AP补体激活小分子抑制剂进行进一步的功能和动力学研究，并确定其特异性蛋白靶点。具体目标2。我们将使用基于硅的高通量分子筛选和基于结构的分子设计工具来开发基于已识别抑制剂的更有效的化学抑制剂。补体领域的大多数治疗研究都集中在生物制剂（重组蛋白、抗体和阻断肽）上。我们提出的实验有可能产生一类新的AP补体激活的小分子化学抑制剂。这些小分子明显更容易生产，并且不像重组蛋白、抗体等那样具有相同的生物危害，使它们成为治疗各种患者和疾病的理想选择。

DESCRIPTION (provided by applicant): The complement cascade has evolved as a surveillance system in the blood stream against pathogens. However, activated complement is a double-edged sword that has the potential to cause significant damage to host tissues. Therefore under normal conditions, complement activation is tightly controlled by a number of regulatory proteins. Defective function of such regulatory proteins causes complement-dependent tissue injury and pathology. Several human diseases have recently been linked to dysregulated alternative pathway (AP) complement activity. Among them, the dry form of age-related macular degeneration (AMD), a common eye disorder affecting millions of elderly Americans that can lead to complete loss of eyesight. Atypical hemolytic uremic syndrome (aHUS) is another genetic disease that is characterized by hemolysis, thrombotic microangiopathy and kidney failure. Both of these disorders are associated with mutations in a key AP complement regulator protein, factor H, leading to uncontrolled AP complement activation and inflammatory injury in the retina and the endothelium, respectively. These conditions are difficult to treat due to the lack of appropriate therapies at the present time. We hypothesize that the development of effective AP inhibitors would help to control complement activation, thereby reducing inflammation and the progression of pathology in these diseases. In this exploratory research project, we will take advantage of the recent crystallization and structural determination of key AP complement proteins and use this knowledge to aid in computer-based drug design. For this goal, we propose to use a combination of high throughput screening and in silico computer-aided molecule design to identify and develop small molecule inhibitors of the AP that could be further developed into therapeutic agents for AMD, aHUS and other AP complement-dependent inflammatory diseases. We will pursue two specific aims: Specific Aim 1. We will perform further functional and kinetic studies of an identified small molecule inhibitor of AP complement activation and determine its specific protein target(s). Specific Aim 2. We will use in silico high-throughput molecular screening and structure-based molecular design tools to develop more effective chemical inhibitors based on the identified inhibitor. Most therapeutic studies in the complement field are focused on biologicals (recombinant proteins, antibodies and blocking peptides). Our proposed experiments have the potential to produce a novel class of small molecule chemical inhibitors of AP complement activation. These small molecules are significantly easier to produce and do not have the same biological hazards as recombinant proteins, antibodies, etc., making them far ideal for the affordable treatment of a wide variety of patients and diseases. PUBLIC HEALTH RELEVANCE: Our research goal is to develop a novel class of small chemical inhibitors of the immune system. Such inhibitors would fill a critical absence in the current ability to prevent or treat auto-immune and inflammatory conditions and represent an important advance to human health.