DESIGN OF POTENT COMPETITIVE INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME - CARBOXYALKANOYL AND MERCAPTOALKANOYL AMINO-ACIDS
DESIGN OF POTENT COMPETITIVE INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME - CARBOXYALKANOYL AND MERCAPTOALKANOYL AMINO-ACIDS
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DOI：
10.1021/bi00644a014
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发表时间：
1977-01-01
期刊：
影响因子：
2.9
通讯作者：
ONDETTI, MA
中科院分区：
文献类型：
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作者：
CUSHMAN, DW;CHEUNG, HS;ONDETTI, MA
利用血管紧张素转换酶活性位点的假设模型[EC 3.4.15.1]来指导特异性抑制剂的设计和合成。与牛羧肽酶A类似，血管紧张素转换酶[兔肺酶]的活性位点包含3个参与肽底物结合的重要基团：一个羧基结合基团，一个与c端肽键亲和的基团，以及一个与倒数第二个（可剪切）肽键羰基配合的紧密结合的Zn2+。根据该模型，琥珀酰氨基酸可以分别通过其氨基酸羧基、酰胺键和琥珀酰羧基与这些结合基相互作用，从而作为酶的特异性竞争性抑制剂。琥珀酰- l-脯氨酸是这样的抑制剂（I50[中位抑制]= 330 .mu）。M)，并尝试优化模型中提出的与酶活性位点的相互作用，合成了d -2-甲基琥珀酰- l-脯氨酸（R，S） （Ki = 2.5 .mu）。M)和d -2-甲基戊二酰- l-脯氨酸（R，S） （Ki = 0.8 μ M）。这些化合物的琥珀基羧基被巯基取代导致了一系列非常有效的竞争性血管紧张素转换酶抑制剂，包括3-巯基丙酰- l-脯氨酸（SQ 13 863, Ki = 0.012 .mu）。M)和d -3-巯基-2-甲基丙酰- l-脯氨酸（S，S） （SQ 14 225, Ki = 0.0017 . μ M）。这些化合物也是有效的口服活性血管紧张素转换酶抑制剂，作为抗高血压药物具有很大的潜力。
A hypothetical model of the active site of angiotensin-converting enzyme [EC 3.4.15.1] was utilized to guide the design and synthesis of specific inhibitors. By analogy to bovine carboxypeptidase A, the active site of angiotensin-converting enzyme [rabbit lung enzyme was used] proposed to contain 3 important groups that participate in binding of peptide substrates: a carboxyl-binding group, a group with affinty for the C-terminal peptide bond, and a tightly bound Zn2+ that could coordinate with the carbonyl of the penultimate (scissile) peptide bond. According to the model, a succinyl amino acid could interact with each of these binding groups via its amino acid carboxyl, amide bond and succinyl carboxyl, respectively, and thus act as a specific competitive inhibitor of the enzyme. Succinyl-L-proline was such an inhibitor (I50 [median inhibition] = 330 .mu.M), and attempts to optimize its interaction with the active site of the enzyme as proposed in the model led to the synthesis of D-2-methylsuccinyl-L-proline (R,S) (Ki = 2.5 .mu.M), and D-2-methylglutaryl-L-proline (R,S) (Ki = 0.8 .mu.M). Replacement of the succinyl carboxyl group of these compounds by a sulfhydryl group led to a series of extremely potent competitive inhibitors of angiotensin-converting enzyme, including 3-mercaptopropanoyl-L-proline (SQ 13 863, Ki = 0.012 .mu.M) and D-3-mercapto-2-methylpropanoyl-L-proline (S,S) (SQ 14 225, Ki = 0.0017 .mu.M). These compounds are also potent orally active inhibitors of angiotensin-converting enzyme and have great potential as antihypertensive agents.