PEPTIDE-BASED INHIBITORS OF HUMAN COMPLEMENT

描述：该计划的长期目标是开发小分子 临床使用的补体抑制剂。人体血液中的补体 在人体对外来细胞入侵的反应中起着关键作用。而当 补体缺乏会导致反复感染和自身免疫性疾病， 不适当和不受控制的补体激活也可能是有害的， 导致许多急性和慢性炎症，包括 缺血/再灌注损伤、类风湿性关节炎和阿尔茨海默病。 补体成分C3和C5在补体级联中占据焦点， 目前所有开发抗补体药物的商业努力都是 因此针对这两种蛋白质中的一种。 他们最近在C5中发现了一个对瞬变至关重要的结合位点 由负责激活C5的蛋白水解酶识别。然后，他们使用 该结合位点的序列以设计阻断C5的接口肽 与蛋白水解酶结合。在此应用程序中，他们建议使用常规 多肽的合成和修饰方法系统地改变 结构以提高其作为补体抑制物的活性。 开发一种更有效的衍生物可能会直接导致临床上 有用的小分子抗补体药物。 建议的商业应用：不可用

DESCRIPTION: The long-term goal of this program is to develop small molecule inhibitors of complement for clinical use. Complement in the human bloodstream plays a key role in the body's response to invasion by foreign cells. While complement deficiency can lead to recurrent infections and autoimmune diseases, inappropriate and uncontrolled complement activation can be harmful as well, contributing to many acute and chronic inflammatory conditions including ischemia/reperfusion injury, rheumatoid arthritis, and Alzheimer's disease. Complement components C3 and C5 occupy focal points in the complement cascade, and all current commercial efforts to develop anti-complement drugs are therefore directed at one of these two proteins. They recently identified a binding site in C5 that is essential for transient recognition by the protease responsible for activating C5. They then used the sequence of this binding site to design an interface peptide that blocks C5 binding to the protease. In this application, they propose to use conventional peptide synthesis and modification methods to systematically alter the structure of this peptide to improve its activity as a complement inhibitor. Development of a more potent derivative may lead directly to a clinically useful small molecule anticomplement drug. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE