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

血管紧张素I转换酶（ACE）抑制剂是目前广泛应用于治疗高血压、心力衰竭、冠心病、纤维化和肾功能衰竭等心血管疾病的药物。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。虽然市场上有许多阻断两个结构域的ACE抑制剂，但没有药物选择性地抑制N结构域，从而产生减少心脏、肾脏和肺中的纤维化和炎症的优点，而没有由阻断C结构域诱导的伴随副作用。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（相当于体细胞ACE的C结构域）和体细胞ACE的N结构域，使用X-射线晶体学提供了真正的基于结构的ACE抑制剂的设计平台。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更严格地利用结构域之间的差异铺平了道路。我们建议的实验是针对全长体细胞ACE和ACE与结构域选择性抑制剂结合的基础和翻译研究的一个重要的医学问题的复合物的晶体结构的结构研究。

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.