title: Chemical insight into the emergence of influenza virus strains that are resistant to Relenza.
abstract: A reagent panel containing ten 4-substituted 4-nitrophenyl α-D-sialosides and a second panel of the corresponding sialic acid glycals were synthesized and used to probe the inhibition mechanism for two neuraminidases, the N2 enzyme from influenza type A virus and the enzyme from Micromonospora viridifaciens. For the viral enzyme the logarithm of the inhibition constant (Ki) correlated with neither the logarithm of the catalytic efficiency (kcat/Km) nor catalytic proficiency (kcat/Km kun). These linear free energy relationship data support the notion that these inhibitors, which include the therapeutic agent Relenza, are not transition state mimics for the enzyme-catalyzed hydrolysis reaction. Moreover, for the influenza enzyme, a correlation (slope, 0.80 ± 0.08) is observed between the logarithms of the inhibition (Ki) and Michaelis (Km) constants. We conclude that the free energy for Relenza binding to the influenza enzyme mimics the enzyme-substrate interactions at the Michaelis complex. Thus, an influenza mutational response to a 4-substituted sialic acid glycal inhibitor can weaken the interactions between the inhibitor and the viral neuraminidase without a concomitant decrease in free energy of binding for the substrate at the enzyme-catalyzed hydrolysis transition state. The current findings make it clear that new structural motifs and/or substitution patterns need to be developed in the search for a bona fide influenza viral neuraminidase transition state analogue inhibitor.
authors.affiliation: Department of Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Fahimeh S
authors.initials: FS
authors.lastname: Shidmoossavee
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Watson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bennet
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008847:Micromonospora / Q000201:enzymology; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir