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

C3/C5 转化酶抑制剂作为一类新型抗炎药物

• 批准号: nhmrc : 301178
• 负责人: John Abbenante
• 金额: $ 31.06万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/c3c5-convertase-inhibitors-inflammatory-drugs/98682
• 关键词: C3; C5; Convertase; Inhibitors; New

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.

许多严重的炎性疾病，如关节炎、败血性休克、肺休克、心脏病、动脉粥样硬化、多发性硬化，用目前可用的药物控制得很差。有大量的证据表明，人类血液中天然存在的补体蛋白参与加剧这些和许多其他人类疾病，但没有好的药物可以抵消它们的影响。被称为C3 a、C5 a和MAC（膜攻击复合物）的三种补体蛋白被认为是在炎症和免疫疾病的发展早期由人体合成的补体系统的特别关键的组分。可以阻断人C3 a、C5 a和MAC形成的新化合物被期望：（a）引导我们更好地理解这些蛋白质如何作用于免疫细胞以及它们在对感染和损伤的免疫应答中各自的作用，和（B）使得能够快速开发用于治疗自身免疫和炎性疾病的全新类别的药物。在NHMRC资助的其他工作中，我们开发了选择性阻断人C3 a或C5 a作用的化合物（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剂。在这个项目中，我们将设计和开发小分子，阻止酶（C3-C5转化酶），使C3 a，C5 a和其他补体蛋白，包括MAC。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。我们将证明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。我们希望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，而不是像目前的药物那样治疗症状。