PEPTIDE-BASED INHIBITORS OF HUMAN COMPLEMENT

描述：该计划的长期目标是开发小分子 临床应用的补体抑制剂。人体血液中的补体 在机体对外来细胞入侵的反应中起着关键作用。而 补体缺乏可导致复发性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性疾病，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占据补体级联中的焦点， 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。 他们最近发现了C5中的一个结合位点，该位点对于短暂的 通过负责激活C5的蛋白酶的识别。然后他们使用了 该结合位点的序列来设计阻断C5的界面肽 与蛋白酶结合。在本申请中，他们建议使用常规的 肽合成和修饰方法，以系统地改变 该肽的结构以提高其作为补体抑制剂的活性。 开发更有效的衍生物可能直接导致临床上 有用的小分子抗补体药物。 拟议商业应用：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