title: Discovery of picomolar slow tight-binding inhibitors of alpha-fucosidase.
abstract: 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.
authors.affiliation: The Genomic Research Center and Institute of Biological Chemistry, Academia Sinica, No. 128 Academia Road Section 2, Nan-Kang, Taipei 11529, Taiwan.
authors.forename: Chuan-Fa
authors.initials: CF
authors.lastname: Chang
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Ho
authors.forename: Chung-Yi
authors.initials: CY
authors.lastname: Wu
authors.forename: Tsrong-An
authors.initials: TA
authors.lastname: Chao
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Lin
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003352:Corynebacterium / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D013050:Spectrometry, Fluorescence; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C483525:fuconojirimycin; D017485:1-Deoxynojirimycin; D005644:alpha-L-Fucosidase; D005944:Glucosamine