Chemical Insight into the Emergence of Influenza Virus Strains That Are Resistant to Relenza

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• 作者：Fahimeh S. Shidmoossavee ; Jacqueline N. Watson ; Andrew J. Bennet
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：September 11, 2013
• 年：2013
• 卷：135
• 期：36
• 页码：13254-13257
• 全文大小：290K
• 年卷期：v.135,no.36(September 11, 2013)
• ISSN：1520-5126

文摘

A reagent panel containing ten 4-substituted 4-nitrophenyl 伪-<span class="smallcaps">dspan>-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 (K<sub>isub>) correlated with neither the logarithm of the catalytic efficiency (k<sub>catsub>/K<sub>msub>) nor catalytic proficiency (k<sub>catsub>/K<sub>msub>k<sub>unsub>). 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 卤 0.08) is observed between the logarithms of the inhibition (K<sub>isub>) and Michaelis (K<sub>msub>) constants. We conclude that the free energy for Relenza binding to the influenza enzyme mimics the enzyme鈥搒ubstrate 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.