Mores Andreas, Matziari Magdalini, Beau Fabrice, Cuniasse Philippe, Yiotakis Athanasios, Dive Vincent
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou 15771, Athens, Greece.
J Med Chem. 2008 Apr 10;51(7):2216-26. doi: 10.1021/jm701275z. Epub 2008 Mar 7.
Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by evaluating a series of phosphinic di- and tripeptides of the general formula: Z-Xaa(PO 2-CH 2)YaaOH and Ac-Zaa-Xaa(PO 2-CH 2)YaaOH. The most potent inhibitor in this series is a tripeptide that displays a K i value of 0.4 nM toward ACE2 and is 3 orders of magnitude less potent toward carboxypeptidase A. Phosphinic tripeptides exhibit high potency exclusively when the Xaa position is occupied by a pseudoproline. A model of interaction between one inhibitor of this series and ACE2 suggests that the critical role played by a proline in inhibitors, but also for substrates hydrolysis, may rely on the presence of Tyr (510) in the ACE2 active site.
血管紧张素转换酶2（ACE2）是最近发现的血管紧张素转换酶的人类同源物，是一种锌金属羧肽酶，可能在心血管和肾功能中发挥独特作用。在此我们报告了ACE2强效和选择性抑制剂的发现，这些抑制剂是通过评估一系列通式为：Z-Xaa(PO₂-CH₂)YaaOH和Ac-Zaa-Xaa(PO₂-CH₂)YaaOH的次膦酸二肽和三肽而确定的。该系列中最有效的抑制剂是一种三肽，其对ACE2的Ki值为0.4 nM，对羧肽酶A的效力低3个数量级。仅当Xaa位置被假脯氨酸占据时，次膦酸三肽才表现出高效力。该系列中一种抑制剂与ACE2之间的相互作用模型表明，脯氨酸在抑制剂中以及对底物水解所起的关键作用可能依赖于ACE2活性位点中Tyr (510)的存在。
