基于鸟氨酰-脯氨酸和赖氨酰-脯氨酸的三肽模拟物作为血管紧张素转换酶抑制剂的构效关系研究
Structure-activity relationship study between Ornithyl-Proline and Lysyl-Proline based tripeptidomimics as angiotensin-converting enzyme inhibitors.
作者信息
Pavar Mahesh Chand, Hanif Kashif, Azam Amir, Lata Sneh, Qadar Pasha M A, Pasha Santosh
机构信息
Peptide Synthesis Lab, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
出版信息
Bioorg Med Chem Lett. 2006 Apr 15;16(8):2117-21. doi: 10.1016/j.bmcl.2006.01.061. Epub 2006 Feb 7.
A designed library of tripeptidomimics of Ornithyl-Proline (Orn-Pro) and Lysyl-Proline (Lys-Pro) conjugated with various unnatural amino acids and carboxylic acid derived heterocyclics was synthesized and screened for possible inhibitors of angiotensin-converting enzyme (ACE). Among the tripeptidomimics 10[MTP-Orn-Pro], 11[HTP-Orn-Pro], 14[TA-Orn-Pro] and 20[BPA-Orn-Pro] showed prominent inhibition with IC50 values in micromolar concentrations. Structure-activity relationship study indicated that C3 side chain of Orn as compared to C4 side chain of Lys at P1' position was better suited to inhibit ACE, with propionic acid (C3) derived heterocyclics and unnatural amino acids.
合成了一个设计库，其中包含与各种非天然氨基酸和羧酸衍生杂环共轭的鸟氨酰 - 脯氨酸（Orn - Pro）和赖氨酰 - 脯氨酸（Lys - Pro）的三肽模拟物，并筛选了它们作为血管紧张素转换酶（ACE）可能的抑制剂。在三肽模拟物中，10[MTP - Orn - Pro]、11[HTP - Orn - Pro]、14[TA - Orn - Pro]和20[BPA - Orn - Pro]表现出显著的抑制作用，IC50值处于微摩尔浓度。构效关系研究表明，与P1' 位置的赖氨酸的C4侧链相比，鸟氨酸的C3侧链更适合与丙酸（C3）衍生的杂环和非天然氨基酸一起抑制ACE。
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