title: Aglycone-focused randomization of 2-difluoromethylphenyl-type sialoside suicide substrates for neuraminidases.
abstract: A selective and potent inhibitor of neuraminidases, a hydrolase that is responsible for processing sialylated glycoconjugates, is a promising drug candidate for various infective diseases. The current study demonstrates that the use of an aglycone-focused library of 2-difluoromethylphenyl α-sialosides is an effective technique to find potent and selective mechanism-based labeling reagents for neuraminidases. The focused library was constructed from a 4-azide-2-difluoromethylphenyl sialoside (2) and an alkyne-terminated compound library by a click reaction. The focused library showed different inhibition patterns for two neuraminidases, Vibrio cholerae neuraminidase (VCNA) and human neuraminidase 2 (hNeu2), and the most potent inhibitors for each neuraminidase were selected. A kinetic analysis of the selected inhibitors demonstrated that the modification of the aglycone moiety improved the K(I) value with little change in the t(1/2) value of the enzyme activity relative to the basic skeleton (2).
authors.affiliation: Graduate School of Life Science and the Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, N21, W11, Kita-ku, Sapporo 001-0021, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hinou
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012794:Sialic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014734:Vibrio cholerae / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D006027:Glycosides; D012794:Sialic Acids; D054852:Small Molecule Libraries; D009439:Neuraminidase