Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

被引：40

作者：

Tseng, Po-Sen ^{[1
,2
,3
]}

Ande, Chennaiah ^{[1
]}

Moremen, Kelley W. ^{[3
,4
]}

Crich, David ^{[1
,2
,3
]}

机构：

[1] Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA

[2] Univ Georgia, Dept Chem, Athens, GA 30602 USA

[3] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA

[4] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2023年 / 62卷 / 08期

关键词：

Glycosidase; Iminosugar; Inhibitor; Methyl Group; Side Chain Conformation; TRANSITION-STATE; REACTIVITY; BINDING; 1-DEOXYNOJIRIMYCIN; GLYCOSYLATION; DISSECTION;

D O I：

10.1002/anie.202217809

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6- to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

引用

页数：5

共 30 条

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