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

血管紧张素转换酶(ACE)抑制剂被广泛用于治疗心血管疾病，包括高血压、心力衰竭、冠心病和肾衰竭。然而，现代血管紧张素转换酶抑制剂是由1970年的S和1980年的S开发的，存在着共同的副作用。这凸显了确定血管紧张素转换酶的三维结构和设计更安全有效的第二代血管紧张素转换酶抑制剂复合体/S的重要性。我们成功地利用X射线结晶学测定了人睾丸血管紧张素转换酶的晶体结构(Natesh et al.，2003)和最近的体细胞血管紧张素转换酶N结构域(Corradi et al.，2006)，为真正基于结构的血管紧张素转换酶抑制剂设计提供了平台。这在蛋白水解酶的结构生物学以及更重要的ACE抑制机制方面是一项重大突破。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。我们建议的实验是针对全长体细胞ACE的结构研究，ACE与结构域选择性抑制剂的复合体的晶体结构将通过与SturRock博士(南非)和Cresset Ltd(英国)的合作来确定。

Angiotensin-I converting enzyme (ACE) inhibitors are widely used to treat cardiovascular diseases, including high blood pressure, heart failure, coronary artery disease and kidney failure. However, current-generation ACE inhibitors, which were developed in the 1970?s and 1980?s, are hampered by common side effects. 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 (Natesh et al., 2003) and recently the N-domain of somatic ACE (Corradi et al., 2006) 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 rigourous 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 will be determined through a collaborative effort with Dr. Sturrock (UCT, South Africa) and Cresset Ltd (UK).