title: A benzoic acid inhibitor induces a novel conformational change in the active site of Influenza B virus neuraminidase.
abstract: Owing to the highly conserved nature of its active site, Influenza B virus neuraminidase (NA) has emerged as a major target for the design of novel anti-influenza drugs. A benzene-ring scaffold has been used in place of the pyranose ring of sialic acid to develop simpler NA inhibitors that contain a minimal number of chiral centers. A new compound belonging to this series, BANA 207, showed significant improvement in inhibitory activity against Influenza B virus NA compared with its parent compound. Here, the structural analysis of a complex of BANA 207 with influenza virus B/Lee/40 NA is reported. The results indicate that BANA 207 forms an unexpected interaction with the crucial active-site residue Glu275 that stabilizes the side chain of this residue in a conformation previously unobserved in NA-inhibitor complexes. This change in the side-chain orientation of Glu275 alters the topology of the triglycerol pocket, which accommodates an additional lipophilic substitution at the benzene ring and may provide an explanation for the increased activity of BANA 207 against Influenza B virus NA.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Lommer
authors.forename: Shoukath M
authors.initials: SM
authors.lastname: Ali
authors.forename: Saroj N
authors.initials: SN
authors.lastname: Bajpai
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Brouillette
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Air
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology*; D019817:Benzoic Acid / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry; D018360:Crystallography, X-Ray; D004583:Electrons; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006860:Hydrogen Bonding; D009981:Influenza B virus / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D009439:Neuraminidase / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000494:pharmacology*; D014771:Virion / Q000378:metabolism
chemical_list: D062365:Aminobenzoates; C495580:BANA 207; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; D018698:Glutamic Acid; D019817:Benzoic Acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid; D005990:Glycerol