Structure-function studies on human Angiotensin-I converting enzyme (ACE)

人血管紧张素-I 转换酶 (ACE) 的结构功能研究

• 批准号: MR/M026647/1
• 负责人: Ravi Acharya
• 金额: $ 75.85万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM026647%2F1
• 关键词: Structure; function; studies; human; Angiotensin

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. The N- and C-domains of ACE display different substrate specificities. 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 (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. The N- and C-domains of ACE display different substrate specificities. 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 (with various clinically important inhibitors as well as novel domain selective inhibitors) using X-ray crystallography have provided the platform for true structure-based design of better 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. Thus the sustained effort on ACE has provided a firm platform for our group for the new studies. Our proposed experiments that builds on a body of previous and current work 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 an important medical problem. In the longer term, the application seeks to exploit detailed structural knowledge for the synthesis of new ACE inhibitors with the aim of providing better drugs for the treatment of cardiovascular diseases in particular hypertension and fibrosis. A key feature will be the design of compounds that are specific for the N- or C-terminal domain of ACE with the expectation that this will provide selective compounds for therapy with fewer side effects.

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，在20世纪70年代和80年代开发的当前一代ACE抑制剂受到常见副作用的阻碍。ACE的N-和C-结构域显示不同的底物特异性。 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（相当于体细胞ACE的C-结构域）和体细胞ACE（血管紧张素-I转化酶[ACE，包含两个结构域（N和C）]抑制剂的N-结构域）的晶体结构，该抑制剂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，在20世纪70年代和80年代开发的当前一代ACE抑制剂受到常见副作用的阻碍。ACE的N-和C-结构域显示不同的底物特异性。 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。我们的成功，在确定的晶体结构的人睾丸ACE（相当于C结构域的体细胞ACE）和N-结构域的体细胞ACE（与各种临床上重要的抑制剂以及新的域选择性抑制剂），使用X-射线晶体学提供了一个平台，真正的结构为基础的设计更好的ACE抑制剂。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。因此，对ACE的持续努力为我们的团队进行新的研究提供了坚实的平台。我们提出的实验，建立在一个机构的以前和目前的工作是针对全长体细胞ACE和ACE与结构域选择性抑制剂的复合物的晶体结构的结构研究相结合的基础和翻译研究的一个重要的医学问题。 从长远来看，该申请寻求利用详细的结构知识来合成新的ACE抑制剂，目的是提供更好的药物来治疗心血管疾病，特别是高血压和纤维化。一个关键特征将是设计对ACE的N-或C-末端结构域具有特异性的化合物，期望这将为治疗提供具有较少副作用的选择性化合物。

项目成果

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

• DOI: 10.1021/acs.jmedchem.1c01924
• 发表时间: 2022-02-24
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Arendse, Lauren B.;Cozier, Gyles E.;Sturrock, Edward D.
• 通讯作者: Sturrock, Edward D.

Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat.

• DOI: 10.1111/febs.16543
• 发表时间: 2022-11
• 期刊: The FEBS journal

Angiotensin-converting enzyme open for business: structural insights into the subdomain dynamics.

• DOI: 10.1111/febs.15601
• 发表时间: 2021-04
• 期刊: The FEBS journal
• 作者: Cozier GE;Lubbe L;Sturrock ED;Acharya KR
• 通讯作者: Acharya KR

Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.

• DOI: 10.1111/febs.14421
• 发表时间: 2018-04
• 期刊: The FEBS journal
• 作者: Cozier GE;Schwager SL;Sharma RK;Chibale K;Sturrock ED;Acharya KR
• 通讯作者: Acharya KR

The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.

设计和开发一种有效且选择性的新型二丙酰衍生物，可与血管紧张素-I 转换酶的 N 结构域结合。

• DOI: 10.1021/acs.jmedchem.7b01478
• 发表时间: 2018
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Fienberg S