A Cyclosporin Derivative Discriminates between Extracellular and Intracellular Cyclophilins
A Cyclosporin Derivative Discriminates between Extracellular and Intracellular Cyclophilins
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DOI：
10.1002/anie.200904529
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Fischer, Gunter
中科院分区：
文献类型：
--
作者：
Malesevic, Miroslav;Kuehling, Jan;Fischer, Gunter
药理学下调酶活性的挑战之一是确保抑制剂靶标的分子性质和器官内定位的选择性。环孢菌素A（CsA）是亲环素（Cyp）样肽基脯氨酰顺式/反式异构酶（PPIases，EC 5.2）的相当混杂的紧密结合抑制剂。1.8)其不能区分细胞外和细胞内Cyp，也不能区分各种人类同种型。此外，已注意到CsA的生理功能与至少两种单独的作用模式一致：1）阻断底物蛋白中脯氨酰键的催化构象相互转化，和2）当作为CypA/CsA二元复合物存在时抑制蛋白磷酸酶钙调磷酸酶（CaN）。[1，2]后一种途径被认为是
One of the challenges in the pharmacological down-regulation of enzyme activity is to assure selectivity in terms of the molecular nature and intraorganismic localization of the inhibitor target. Cyclosporin A (CsA) exemplifies a rather promiscuous tight-binding inhibitor of the cyclophilin (Cyp)-like peptidyl prolyl cis/trans isomerases (PPIases, EC 5.2. 1.8) that is unable to distinguish between extracellular and intracellular Cyp, nor between the various human isoforms. In addition, physiological functions of CsA have been noted that are consistent with at least two separate modes of action: 1) blocking catalyzed conformational interconversions of prolyl bonds in substrate proteins, and 2) inhibiting the protein phosphatase calcineurin (CaN) when present as a CypA/CsA binary complex.[1, 2] The latter pathway is thought to be