Epoxysuccinyl dipeptides as selective inhibitors of cathepsin B.
Epoxysuccinyl dipeptides as selective inhibitors of cathepsin B.
复制标题
环氧琥珀酰二肽作为组织蛋白酶 B 的选择性抑制剂。
DOI：
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发表时间：
1993
影响因子：
7.3
通讯作者：
R. Ménard
中科院分区：
文献类型：
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作者：
B. Gour;P. Lachance;C. Plouffe;A. C. Storer;R. Ménard
E-64的环氧琥珀酰二肽类似物（R- epsleupro -R‘）（图1）已被合成，其环氧环上的羧酸基或游离（R = OH）或转化为酯或酰胺（R = EtO或i-BuNH）， c端氨基酸脯氨酸或被阻断（R’ = OBzl）或游离（R' = OH）。这些化合物被用来研究最近报道的这种类型的抑制剂对溶酶体半胱氨酸蛋白酶组织蛋白酶B的选择性。结果表明，只有当环氧环上羧酸盐的衍生化与带有自由负电荷c端残基的二肽基结合时，才赋予组织蛋白酶B比木瓜蛋白酶的选择性。有人提出，这种选择性反映了与位于组织蛋白酶B的引物亚位的环上的组氨酸残基的相互作用，该环为抑制剂的c端羧酸基提供了带正电的锚点。在木瓜蛋白酶家族的其他半胱氨酸蛋白酶中没有发现组织蛋白酶B的引物亚位点环，这为设计半胱氨酸蛋白酶抑制剂的选择性提供了独特的模板。
Epoxysuccinyl dipeptide analogs of E-64 (R-EpsLeuPro-R') (Figure 1) have been synthesized with the carboxylate group on the epoxide ring either free (R = OH) or converted to an ester or an amide (R = EtO or i-BuNH) and with the C-terminal amino acid proline either blocked (R' = OBzl) or free (R' = OH). These compounds were used to investigate the recently reported selectivity of this type of inhibitor for the lysosomal cysteine protease cathepsin B. It was shown that derivatization of the carboxylate on the epoxide ring confers selectivity for cathepsin B over papain only when it is combined to a dipeptidyl moiety with a free negatively charged C-terminal residue. It is proposed that this selectivity reflects interactions with histidine residues on a loop located in the primed subsites of cathepsin B which provides a positively charged anchor for the C-terminal carboxylate group of the inhibitor. The primed subsite loop of cathepsin B is not found in other cysteine proteases of the papain family and offers a unique template for designing selectivity in cysteine protease inhibitors.