title: Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses.
abstract: Unlike the group-2 neuraminidase, the group-1 neuraminidase of influenza virus possesses a flexible loop (the 150-loop) and a cavity (the 150-cavity) adjacent to the active site, and renders a conformational change from the 'open' form to the 'closed' form on binding with substrate (sialo-glycoprotein) or inhibitor (e.g., zanamivir). Zanamivir derivative 8a having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidino group is designed as a possible inhibitor on the basis of computer docking to the open form of N1 subtype neuraminidase. Indeed, compound 8a exhibits strong neuraminidase inhibition and good anti-influenza activity against H1N1 virus with IC(50)=2.15microM and EC(50)=0.77microM, respectively. This study may provide a clue to future design of better group-1 neuraminidase inhibitors.
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Wen-Hsien
authors.initials: WH
authors.lastname: Wen
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Wang
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.forename: Yih-Shyun E
authors.initials: YS
authors.lastname: Cheng
authors.forename: An-Suei
authors.initials: AS
authors.lastname: Yang
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry; D053118:Influenza A Virus, H1N1 Subtype; D020128:Inhibitory Concentration 50; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir