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

血管紧张素I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、冠状动脉疾病和肾衰竭。然而，目前的一代ACE抑制剂，这是在1970年开发的？S和1980？s，受到常见副作用的阻碍。这强调了确定ACE的3D结构和设计更安全和更有效的第二代ACE抑制剂复合物的重要性。我们成功地确定了人睾丸ACE的晶体结构（Natesh等人，2003）和最近的体细胞ACE的N-结构域（Corradi等人，2006）使用X射线晶体学为ACE抑制剂的真正基于结构的设计提供了平台。这是蛋白酶结构生物学方面的重大突破，更重要的是，ACE抑制机制。这为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更严格地利用结构域之间的差异铺平了道路。我们提出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物的晶体结构将通过与Sturrock博士（UCT，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).