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，目前的药物控制不佳。有大量证据表明，人类血液中自然产生的补体蛋白与这些疾病和许多其他人类疾病的恶化有关，但目前还没有好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性和免疫性疾病早期合成的补体系统的关键成分。可以阻止人类C3a、C5a和MAC形成的新化合物有望：(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各自的作用，以及(B)使一种全新的治疗自身免疫性和炎症性疾病的药物得以快速开发。目前还没有基于补体的药物可用于人类。在NHMRC资助的其他工作中，我们开发了选择性阻断人类C3a或C5a活动的化合物(拮抗剂)，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药。在这个项目中，我们将设计和开发阻止C3a、C5a和包括MAC在内的其他补体蛋白的酶(C3-C5转换酶)的小分子。我们预计，这种抑制剂将是更有效的抗炎药物，因为它们将阻止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。我们预计C3-C5转换酶抑制剂将是一种全新的抗炎药物，治疗疾病过程，而不是像目前的药物那样的症状。

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.