Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome
Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome
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DOI：
10.1016/j.bmcl.2005.02.013
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发表时间：
2005-04-01
影响因子：
2.7
通讯作者：
Ikeda, D
中科院分区：
文献类型：
--
作者：
Momose, I;Umezawa, Y;Ikeda, D
Tyropeptin A 是一种新型有效的蛋白酶体抑制剂，由 Kitasatospora sp. 产生。 MK993-dF2。为了增强酪肽A的抑制效力，我们构建了酪肽A与负责哺乳动物20S蛋白酶体胰凝乳蛋白酶样活性的位点结合的结构模型。基于这些建模实验，我们设计并合成了酪肽A的几种衍生物。其中，最有效的化合物TP-104，与酪肽A相比，其抑制效力增强了20倍。此外，TP-110特异性抑制胰凝乳蛋白酶样活性，但不抑制PGPH和胰蛋白酶样活性。 (c) 2005 Elsevier Ltd. 保留所有权利。
Tyropeptin A, a new potent proteasome inhibitor, was produced by Kitasatospora sp. MK993-dF2. To enhance the inhibitory potency of tyropeptin A, we constructed the structural model of tyropeptin A bound to the site responsible for the chymotrypsin-like activity of mammalian 20S proteasome. Based on these modeling experiments, we designed and synthesized several derivatives of tyropeptin A. Among them, the most potent compound, TP-104, exhibited a 20-fold enhancement in its inhibitory potency compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the PGPH and the trypsin-like activities. (c) 2005 Elsevier Ltd. All rights reserved.