Schirmeister T
Department of Pharmaceutical Chemistry, Albert-Ludwigs University of Freiburg, Germany.
Biopolymers. 1999;51(1):87-97. doi: 10.1002/(SICI)1097-0282(1999)51:1<87::AID-BIP10>3.0.CO;2-Z.
Mammalian cysteine proteases of the papain superfamily are interesting targets for the development of new drugs against diseases connected to abnormal degradation of muscle or bone proteins. The high nucleophilicity of the active site of these proteases as well as the characteristics of the well-known epoxysuccinic acid derived cysteine protease inhibitors provided a basis for the design of new types of selective and irreversible inhibitors for these enzymes. We designed and synthesized a novel class of peptidic cysteine protease inhibitors containing aziridine-2,3-dicarboxylic acid as electrophilic amino acid. Three types of aziridinyl peptides that differ in the position of the aziridine building block within the peptide chain have been synthesized and tested as inhibitors of several cysteine proteases. Remarkable differences could be observed between the three types of inhibitors concerning their activity, stereospecificity, pH dependency of inhibition, and selectivity between different cysteine proteases, respectively, indicating that different binding modes of the three types of inhibitors in respect to their orientation in the S and S' binding sites of the enzymes may be present.
木瓜蛋白酶超家族的哺乳动物半胱氨酸蛋白酶是开发治疗与肌肉或骨蛋白异常降解相关疾病的新药的有趣靶点。这些蛋白酶活性位点的高亲核性以及众所周知的环氧琥珀酸衍生的半胱氨酸蛋白酶抑制剂的特性为设计新型选择性和不可逆抑制剂提供了基础。我们设计并合成了一类新型的肽类半胱氨酸蛋白酶抑制剂，其中含有氮丙啶-2,3-二羧酸作为亲电氨基酸。合成了三种在肽链中氮丙啶结构单元位置不同的氮丙啶基肽，并将其作为几种半胱氨酸蛋白酶的抑制剂进行了测试。分别在三种抑制剂的活性、立体特异性、抑制的pH依赖性以及不同半胱氨酸蛋白酶之间的选择性方面观察到了显著差异，这表明三种抑制剂在酶的S和S'结合位点的取向方面可能存在不同的结合模式。
