Structural studies on human Angiotensin-I converting enzyme (ACE) and the design of novel domain specific inhibitors

血管紧张素- 1转换酶[ACE，含有两个结构域（N和C）]抑制剂被广泛用于治疗心血管疾病，包括高血压、心力衰竭、冠状动脉疾病、纤维化和肾衰竭。然而，当前一代的ACE抑制剂是在1970年开发的。80年代和80年代？这些药物都有常见的副作用。虽然市场上有许多ACE抑制剂可以阻断这两个结构域，但没有一种药物可以选择性地抑制N结构域，从而获得减少心脏、肾脏和肺部纤维化和炎症的优势，而不会伴随C结构域阻断引起的副作用。这强调了确定ACE三维结构和设计更安全、更有效的第二代ACE抑制剂复合物的重要性。我们利用x射线晶体学成功测定了人类睾丸ACE的晶体结构（相当于体细胞ACE的C结构域）和体细胞ACE的n结构域，为真正基于结构的ACE抑制剂设计提供了平台。这是在蛋白酶的结构生物学方面的重大突破，更重要的是，ACE抑制机制的突破。这为一种更严格的方法铺平了道路，通过基于结构的新型结构域选择性抑制剂的药物设计方法来利用结构域之间的差异。我们提出的实验是针对一个重要的医学问题，结合基础和转化研究，对全长体细胞ACE和ACE与区域选择性抑制剂配合物的晶体结构进行结构研究。

Angiotensin-I converting enzyme [ACE, which contains two domains (N and C)] inhibitors are widely used to treat cardiovascular diseases, including high blood pressure, heart failure, coronary artery disease, fibrosis and kidney failure. However, current-generation ACE inhibitors, which were developed in the 1970?s and 1980?s, are hampered by common side effects. While there are many ACE inhibitors on the market that block both domains, there are no drugs that selectively inhibit the N domain and thereby accrue the advantages of reducing fibrosis and inflammation in the heart, kidney and lung, without the concomitant side effects induced by blockade of the C domain.. This underscores the importance of the determination of the 3D structure of ACE and the design of 2nd generation ACE-inhibitor complex/s that are safer and more effective. Our success in the determination of the crystal structure of human testis ACE (equivalent to the C domain of somatic ACE) and the N-domain of somatic ACE using X-ray crystallography have provided the platform for true structure-based design of ACE inhibitors. This is a significant breakthrough in terms of the structural biology of the protease and, more importantly, the mechanism of ACE inhibition. This paves the way for a more rigorous approach exploiting the differences between the domains through a structure based drug design approach of novel domain-selective inhibitors. Our proposed experiments are directed at structural study of the full-length somatic ACE and crystal structures of complexes of ACE with domain selective inhibitors combining basic and translational research on a important medical problem.