C3/C5 Convertase Inhibitors As A New Class Of Anti-Inflammatory Drugs

许多严重的炎症性疾病，如关节炎、感染性休克、肺休克、心脏病、动脉粥样硬化、多发性硬化症，目前可用的药物控制得很差。有大量证据表明，人类血液中天然存在的补体蛋白会加剧这些疾病和许多其他人类疾病，但目前还没有有效的药物来抵消它们的影响。三种补体蛋白C3a， C5a和MAC（膜攻击复合体）被认为是人体在炎症和免疫疾病发展早期合成的补体系统中特别关键的组成部分。预计能够阻断人类C3a、C5a和MAC形成的新化合物：(a)使我们更好地了解这些蛋白质如何作用于免疫细胞以及它们在感染和损伤的免疫反应中的各自作用，以及(b)使我们能够迅速开发出治疗自身免疫性和炎症性疾病的全新一类药物。目前还没有基于补充的药物可用于人类。在其他NHMRC资助的工作中，我们开发了化合物（拮抗剂），可以选择性地阻断人类C3a或C5a的作用，并表明它们在许多炎症性疾病的大鼠模型中是有效的抗炎剂。在这个项目中，我们将设计和开发小分子，阻断制造C3a， C5a和其他补体蛋白（包括MAC）的酶（C3-C5转化酶）。我们期望这种抑制剂将成为更有效的抗炎药物，因为它们将阻断多种补体蛋白的形成，每种补体蛋白都具有促炎活性。我们将展示新化合物对补体成分的选择性作用，并在炎症性疾病的大鼠模型中进行测试。我们期望C3-C5转化酶抑制剂成为一种全新的抗炎药物，治疗疾病过程而不是像现有药物那样治疗症状。

Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of the complement system synthesized by the human body early in the development of inflammatory and immune diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To lead us to a better understanding of how these proteins act on immune cells and of their respective roles in the immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available in man. In other NHMRC funded work we have developed compounds (antagonists) that selectively block the actions of human C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a number of inflammatory diseases. In this project we will design and develop small molecules that block the enzymes (C3-C5 convertases) that make C3a, C5a and other complement proteins including MAC. We expect that such inhibitors will be even more effective antinflammatory drugs because they will block formation of multiple complement proteins that each have proinflammatory activity. We will demonstrate selective effects of the new compounds on components of complement, and test them in rat models of inflammatory diseases. We expect C3-C5 convertase inhibitors to be a completely new type of anti-inflammatory drug, treating disease processes rather than symptoms like current drugs.