Development of Small Molecule Inhibitors of the Classical Complement Pathway

人类补体系统是一套受到严格调控的~30个血清或膜结合的系统 蛋白质，最为人所知的是它作为抵御微生物入侵的第一道防线的作用。一位现代人 视野位置是许多重要生理过程的补充，包括 适应性免疫串扰，发育作用，以及作为维持体内平衡的关键角色。 大量人类自身免疫性、炎症性和神经退行性疾病现在被联系在一起 由于失去了对补体级联的微调控制。最近，监管机构的失调 经典补体途径已被证明在阿尔茨海默病小鼠模型中起因果作用 疾病。目前有500万美国人患有阿尔茨海默氏症，预计将有14 到2050年，迫切需要开发新的治疗方法。不幸的是，临床上 补体导向药物的流水线目前不足以生产治疗 经典的通路驱动的神经退行性疾病。为了满足这一需求，这个的根本目标是 项目是开发高质量、高特异性的经典补体小分子抑制剂 路径。 补体的第一组分，c1，是经典途径的多亚基酶原 并由单分子C1q与丝氨酸蛋白酶异四聚体C1r2C1s2组成。 C1R是该途径的起始酶，具有需要分子背景的独特特征 以执行其唯一已知的生理功能(即激活经典通路)。在这 我们将尝试通过识别结合C1R的小分子来利用这一分子供应 这会破坏c1的稳定性。为了实现这一点，我们将使用基于片段的药物设计和自然 以产品为灵感的化学库与基于表面等离子体共振的筛选相结合 方法论。然后，我们将实施一种新的策略来分离具有高C1r特异性的化合物 和很高的补体抑制潜力。最后，将使用x射线结晶学来揭示这种结合。 优先命中化合物的模式。该项目将为基于结构的药物提供框架 为开发治疗经典型肺炎的新型补体导向疗法所做的设计努力 与路径相关的人类疾病，如阿尔茨海默病。

The human complement system is a tightly regulated set of ~30 serum or membrane-bound proteins which is best known for its role as a ‘first-line-of-defense’ against microbial intruders. A modern view places complement at the center of a number of important physiological processes including adaptive immunity crosstalk, developmental roles, and as a critical player in maintaining homeostasis. A large number of human autoimmune, inflammatory, and neurodegenerative diseases are now linked to the loss of the fine-tuned control of the complement cascade. Recently, the dysregulation of the classical complement pathway has been shown to play a causal role in murine models of Alzheimer’s disease. With 5 million Americans currently suffering from Alzheimer’s disease, and a predicted 14 million by 2050, development of new treatments is desperately needed. Unfortunately, the clinical pipeline of complement-directed drugs is currently inadequately positioned to produce therapies for classical pathway-driven neurodegenerative conditions. To meet this need, the fundamental goal of this project is to develop high quality, high specificity small molecule inhibitors of the classical complement pathway. The first component of complement, C1, is the multi-subunit zymogen of the classical pathway and consists a single molecule of C1q in complex with the serine protease heterotetramer C1r2C1s2. C1r is the initiator protease of the pathway and has the unique feature of requiring the molecular context of C1 to carry out its only known physiological function (i.e. activation of the classical pathway). In this project we will attempt to exploit this molecular provision by identifying C1r-binding small molecules which disrupt the stability of C1. To achieve this we will use fragment based drug design and natural product-inspired chemical libraries in combination with an surface plasmon resonance-based screening methodology. We will then implement a novel strategy to isolate compounds with high C1r-specificty and high complement inhibitory potential. Finally, x-ray crystallography will be used to reveal the binding mode of prioritized hit compounds. This project will provide the framework for structure-based drug design efforts for the development of novel complement-directed therapeutics for treatment of classical pathway-related human diseases such as Alzheimer’s disease.