Gour-Salin B J, Lachance P, Plouffe C, Storer A C, Ménard R
Biotechnology Research Institute, Montreal, Quebec, Canada.
J Med Chem. 1993 Mar 19;36(6):720-5. doi: 10.1021/jm00058a008.
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.
已合成了E-64（R-EpsLeuPro-R'）（图1）的环氧琥珀酰二肽类似物，其中环氧环上的羧基可以是游离的（R = OH），也可以转化为酯或酰胺（R = EtO或i-BuNH），并且C末端氨基酸脯氨酸可以是被保护的（R' = OBzl）或游离的（R' = OH）。这些化合物用于研究最近报道的这类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，只有当环氧环上的羧基与带有游离负电荷C末端残基的二肽基部分结合时，其衍生化才会赋予组织蛋白酶B相对于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的引发亚位点环上的组氨酸残基的相互作用，该环为抑制剂的C末端羧基提供了一个带正电荷的锚定位点。在木瓜蛋白酶家族的其他半胱氨酸蛋白酶中未发现组织蛋白酶B的引发亚位点环，它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。
