Development of Small Molecule Inhibitors of the Classical Complement Pathway

经典补体途径小分子抑制剂的开发

基本信息

批准号：
9375741
负责人：
Brandon Lee Garcia
金额：
$ 22.5万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9375741
关键词：
Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model American Antigen-Antibody Complex Apolipoprotein E Astrocytes Autoimmune Process Binding Binding Proteins Binding Sites Biological Assay Borrelia Brain Diseases Classical Complement Pathway Clinical Competitive Binding Complement Complement 1 Inactivators Complement 1q Complement component C1r Complement component C1s Complex Cytolysis Deposition Development Disease Drug Design Enzyme Precursors Event Future Goals Homeostasis Human Immunologic Surveillance In Vitro Inflammatory Intervention Knowledge Lead Libraries Link Maintenance Maps Mediating Membrane Methodology Microglia Modeling Modernization Molecular Molecular Conformation Natural Immunity Natural Products Nerve Degeneration Neurodegenerative Disorders Opsonin Pathology Pathway interactions Pattern Recognition Peptide Hydrolases Phagocytes Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Physiological Processes Plasma Proteins Play Positioning Attribute Recruitment Activity Resolution Role Serine Protease Serine Proteinase Inhibitors Serum Signal Transduction Site Specificity Structure Substrate Specificity Surface Surface Plasmon Resonance Synapses System Technology Therapeutic Therapeutic Intervention Triage X-Ray Crystallography activation product adaptive immunity antimicrobial arm base complement C3 precursor complement pathway complement system drug development drug discovery human disease in vitro Assay inhibitor/antagonist microbial mouse model mutant new therapeutic target novel novel strategies novel therapeutics protein protein interaction scaffold screening senescence single molecule small molecule small molecule inhibitor small molecule libraries synaptic pruning

项目摘要

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.

人类完成系统是一组约30张血清或膜结合的集合蛋白质以其对微生物入侵者的“防御者”角色而闻名。现代在许多重要的物理过程的中心查看位置，包括适应性免疫学串扰，发育角色以及维持体内平衡的关键参与者。现在有大量的人类自身免疫性，炎症和神经退行性疾病损失了完成级联的微调控制。最近，失调经典补体途径已显示在阿尔茨海默氏症的鼠模型中起因果关系疾病。目前有500万美国人患有阿尔茨海默氏病，预计14 到2050年，迫切需要开发新的治疗方法。不幸的是，临床目前，补体指导药物的管道无法实现生产的疗法经典途径驱动的神经退行性条件。为了满足这一需求，这是基本目标项目是为了发展经典完成的高品质，高特异性小分子抑制剂路径。完成的第一个组成部分C1是经典途径的多生Zymogen 并由与丝氨酸蛋白酶异驱精C1R2C1S2的C1Q的单个分子组成。 C1R是该途径的引发剂蛋白酶，具有需要分子环境的独特特征 C1执行其唯一已知的身体功能（即经典途径的激活）。在这个项目我们将尝试通过识别C1R结合小分子来利用这一分子条款破坏了C1的稳定性。为了实现这一目标，我们将使用基于碎片的药物设计和自然产品启发的化学文库与表面等离子体共振的筛选结合方法论。然后，我们将实施一种新颖的策略来隔离C1R特异性高的化合物和高完成抑制潜力。最后，X射线晶体学将用于揭示结合优先级命中化合物的模式。该项目将为基于结构的药物提供框架为开发新颖的完整疗法的设计工作，用于治疗古典与途径有关的人类疾病，例如阿尔茨海默氏病。