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

• 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
• 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' s Disease; Alzheimer' 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

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.

人补体系统是一组严格调节的~30个血清或膜结合补体。 这种蛋白质以其作为对抗微生物入侵者的“第一道防线”而闻名。现代 这种观点将补充剂置于许多重要生理过程的中心，包括 适应性免疫串扰，发展的作用，并作为维持稳态的关键球员。 大量的人类自身免疫性疾病、炎症性疾病和神经退行性疾病现在都与 补体级联的微调控制的损失。最近， 经典的补体途径已被证明在阿尔茨海默氏病的鼠模型中起因果作用 疾病目前有500万美国人患有老年痴呆症， 到2050年，我们迫切需要开发新的治疗方法。不幸的是，临床 补体导向药物的管道目前不足以生产治疗 典型的神经退行性疾病为了满足这一需求，本组织的基本目标是 项目是开发高质量、高特异性的经典补体小分子抑制剂 通路 补体的第一组分C1是经典途径的多亚基酶原 并且由与丝氨酸蛋白酶异源四聚体C1 r2 C1 s2复合的C1 q的单个分子组成。 C1 r是该途径的起始蛋白酶，并且具有需要分子背景的独特特征 C1执行其唯一已知的生理功能（即激活经典途径）。在这 我们将尝试通过鉴定C1 r结合小分子来利用这种分子供应 破坏了C1的稳定性为了实现这一目标，我们将使用基于片段的药物设计和天然药物。 结合基于表面等离子体共振的筛选的产品启发的化学库 方法论然后，我们将实施一种新的策略来分离具有高C1 r特异性的化合物 和高补体抑制潜力。最后，X射线晶体学将用于揭示结合 优先打击化合物的模式。该项目将为基于结构的药物提供框架 用于开发治疗经典的补体介导的新疗法的设计努力 途径相关的人类疾病，如阿尔茨海默病。