Discovery of picomolar slow tight-binding inhibitors of α-fucosidase

被引:60
作者
Chang, CF
Ho, CW
Wu, CY
Chao, TA
Wong, CH
Lin, CH
机构
[1] Acad Sinica, Genom Res Ctr, Taipei 11529, Taiwan
[2] Acad Sinica, Inst Biol Chem, Taipei 11529, Taiwan
[3] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[4] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
来源
CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 09期
关键词
D O I
10.1016/j.chembiol.2004.07.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glycosidase inhibitors have shown great medicinal and pharmaceutical values as exemplified by the therapeutic treatment of influenza virus and non-insulin-dependent diabetes. We herein report the discovery of picomolar slow tight-binding inhibitors 2-5 against the alpha-fucosidase from Corynebacterium sp. by a rapid screening for an optimal aglycon attached to 1-aminomethyl fuconojirimycin (1). The time-dependent inhibition displays the progressive tightening of enzyme-inhibitor complex from a low nanomolar K-i to picomolar K-i* value. Particularly compound 2 with a K-i* of 0.46 pM represents the most potent glycosidase inhibitor to date. The effect of compound 3 on the intrinsic fluorescence of alpha-fucosidase is both time-and concentration-dependent in a saturation-type manner, which is consistent with the initial formation of a rapid equilibrium complex of enzyme and inhibitor (E.I), followed by the slower formation of a tightly bound enzyme-inhibitor complex (E.I*). The binding affinity increases 3.5 x 10(4)-fold from 1 (K-i = 16.3 nM) to 2 (K-i* = 0.46 pM). This work clearly demonstrates the effectiveness of our combinatorial approach leading to the rapid discovery of potent inhibitors.
引用
收藏
页码:1301 / 1306
页数:6
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