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: Fahimeh S Shidmoossavee, Jacqueline N Watson, Andrew J Bennet
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 135 Issue 36 Pg. 13254-7 (Sep 11 2013) ISSN: 1520-5126 [Electronic] United States
• PMID: 24001125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Neuraminidase
• Zanamivir

Topics

• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Drug Resistance, Viral
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Influenza A virus (drug effects, enzymology)
• Microbial Sensitivity Tests
• Micromonospora (enzymology)
• Molecular Conformation
• Neuraminidase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Zanamivir (chemical synthesis, chemistry, pharmacology)