pH dependence of inhibitors targeting the occluding loop of cathepsin B
pH dependence of inhibitors targeting the occluding loop of cathepsin B
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DOI：
10.1016/s0045-2068(02)00009-3
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发表时间：
2002-08-01
影响因子：
5.1
通讯作者：
Rydzewski, RM
中科院分区：
文献类型：
--
作者：
Cathers, BE;Barrett, C;Rydzewski, RM
先前已经基于天然产物半胱氨酸蛋白酶抑制剂E-64合成了有效的和选择性的组织蛋白酶B抑制剂。X射线晶体数据表明，这些化合物通过其游离羧酸盐与位于组织蛋白酶B封闭环内活性位点引物侧的带正电荷的组氨酸残基相互作用。在此，我们研究了两个引物侧结合化合物的pH依赖性。在每种情况下，当pH从4升高到7.8时，k（inact）/K-1急剧下降，对应于pK（a）4.4的单次电离。这些结果表明，如果酶环境的pH大于5.5，则靶向组织蛋白酶B的封闭环可能是不良的抑制剂设计策略。然而，这种类型的抑制剂可能是一个有用的工具，以帮助阐明组织蛋白酶B在侵袭性肿瘤中的作用和环境。(C)2002 Elsevier Science（美国）。All rights reserved.
Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two prime-side-binding compounds. In each case there is a dramatic decrease in k(inact)/K-1 as the pH is raised from 4 to 7.8 corresponding to a single ionization of pK(a) 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors. (C) 2002 Elsevier Science (USA). All rights reserved.