Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition
Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition
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DOI：
10.1021/acs.jmedchem.1c01924
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发表时间：
2022-02-24
影响因子：
7.3
通讯作者：
Sturrock, Edward D.
中科院分区：
文献类型：
--
作者：
Arendse, Lauren B.;Cozier, Gyles E.;Sturrock, Edward D.
选择性地抑制血管紧张素转换酶C结构域(CACE)和奈普利辛(NEP)，使ACE N结构域(NACE)自由降解缓激肽和其他多肽，有可能提供非选择性双重ACE/NEP抑制剂(如奥马曲拉)所观察到的强大的降压和心脏保护益处，而不会增加不良反应的风险。我们基于先前报道的C结构域选择性ACE抑制剂赖氨普利色氨酸(Lisinopriltrophan，LISW)，合成了三种具有纳摩尔效力的1-羧基-3-苯丙基二肽抑制剂，以探索有效的CACE/NEP双重抑制的结构要求。在这里，我们报道了这些与NACE和CACE结合的抑制剂的合成、酶动力学数据和高分辨晶体结构，为推动效力和选择性的因素提供了有价值的见解。总体而言，这些结果强调了S-1‘和S-2’亚基之间相互作用对ACE结构域选择性的重要性，为未来开发CACE/NEP双重抑制剂的化学努力提供了指导。
Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopriltryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S-1' and S-2' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.