New peptidic cysteine protease inhibitors derived from the electrophilic alpha-amino acid aziridine-2,3-dicarboxylic acid.
New peptidic cysteine protease inhibitors derived from the electrophilic alpha-amino acid aziridine-2,3-dicarboxylic acid.
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新型肽类半胱氨酸蛋白酶抑制剂，源自亲电子 α-氨基酸氮丙啶-2,3-二羧酸。
DOI：
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发表时间：
1999
影响因子：
7.3
通讯作者：
T. Schirmeister
中科院分区：
文献类型：
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作者：
T. Schirmeister
在肽链内不同位置含有氮丙啶-2，3-二羧酸（Azi）作为亲电子α-氨基酸的三种不同类型的肽II型，N-未取代的氮杂环丙烷，其中Azi作为N-末端氨基酸; III型，Azi的N-酰化二肽基衍生物已经合成并作为半胱氨酸蛋白酶木瓜蛋白酶、组织蛋白酶B、L和H，以及钙蛋白酶I和II的抑制剂进行了测试，以及抗几种丝氨酸蛋白酶、一种天冬氨酸蛋白酶和一种金属蛋白酶。所有氮丙啶基肽都是特异性半胱氨酸蛋白酶抑制剂。木瓜蛋白酶和组织蛋白酶B和L被不可逆地抑制，而组织蛋白酶H和钙蛋白酶以非时间依赖性方式被抑制。一些化合物被证明是丝氨酸蛋白酶和金属蛋白酶嗜热菌蛋白酶的底物。在三种不同类型的抑制剂之间可以观察到显著的差异，涉及立体特异性、抑制的pH依赖性、不同半胱氨酸蛋白酶之间的选择性以及氮丙啶环上的游离羧酸官能团对于抑制的重要性。尤其是II型抑制剂，众所周知的环氧琥珀酰肽的氮杂类似物，是有效的半胱氨酸蛋白酶抑制剂。除了BOC-Leu-Gly-（S，S+R，R）-Azi-（OEt）2（28 a +B）（一种高选择性和有效的组织蛋白酶L抑制剂）之外，I型N-酰化氮杂环丙烷是比II型或III型化合物更弱的抑制剂。所观察到的结果可以解释为不同的结合模式的三种类型的抑制剂相对于其在S-和S '-结合位点的酶的取向。此外，质子化氮丙啶N的存在改变了II型抑制剂的结合模式。
Three different types of peptides containing aziridine-2, 3-dicarboxylic acid (Azi) as an electrophilic alpha-amino acid at different positions within the peptide chain (type I, N-acylated aziridines with Azi as C-terminal amino acid; type II, N-unsubstituted aziridines with Azi as N-terminal amino acid; type III, N-acylated bispeptidyl derivatives of Azi) have been synthesized and tested as inhibitors of the cysteine proteases papain, cathepsins B, L, and H, and calpains I and II, as well as against several serine proteases, one aspartate, and one metalloprotease. All aziridinyl peptides are specific cysteine protease inhibitors. Papain and cathepsins B and L are inhibited irreversibly, whereas cathepsin H and calpains are inhibited in a non-time-dependent manner. Some compounds turned out to be substrates for serine proteases and for the metalloprotease thermolysin. Remarkable differences can be observed between the three different types of inhibitors concerning stereospecificity, pH dependency of inhibition, selectivity between different cysteine proteases, and the importance of a free carboxylic acid function at the aziridine ring for inhibition. Above all type II inhibitors, aza analogues of the well-known epoxysuccinyl peptides, are potent cysteine protease inhibitors. With the exception of BOC-Leu-Gly-(S, S+R,R)-Azi-(OEt)2 (28a+b), a highly selective and potent cathepsin L inhibitor, N-acylated aziridines of type I are weaker inhibitors than type II or type III compounds. The observed results can be explained by different binding modes of the three types of inhibitors with respect to their orientation in the S- and S'-binding sites of the enzymes. Furthermore, the presence of a protonated aziridine N modifies the binding mode of type II inhibitors.