title: Hydrophobic benzoic acids as inhibitors of influenza neuraminidase.
abstract: Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A new benzoic acid inhibitor (11) containing a lipophilic side chain at C-3 and a guanidine at C-5 was synthesized. The X-ray structure of 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid in complex with NA revealed that the lipophilic side chain binds in a newly created hydrophobic pocket formed by the movement of Glu 278 to interact with Arg 226, whereas the guanidine of 11 interacts in a negatively charged pocket created by Asp 152, Glu 120 and Glu 229. Compound 11 was highly selective for type A (H2N2) influenza NA (IC50 1 microM) over type B (B/Lee/40) influenza NA (IC50 500 microM).
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, 35294, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Atigadda
authors.forename: W J
authors.initials: WJ
authors.lastname: Brouillette
authors.forename: F
authors.initials: F
authors.lastname: Duarte
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.forename: S
authors.initials: S
authors.lastname: Bantia
authors.forename: P
authors.initials: P
authors.lastname: Chand
authors.forename: N
authors.initials: N
authors.lastname: Chu
authors.forename: J A
authors.initials: JA
authors.lastname: Montgomery
authors.forename: D A
authors.initials: DA
authors.lastname: Walsh
authors.forename: E
authors.initials: E
authors.lastname: Sudbeck
authors.forename: J
authors.initials: J
authors.lastname: Finley
authors.forename: G M
authors.initials: GM
authors.lastname: Air
authors.forename: M
authors.initials: M
authors.lastname: Luo
authors.forename: G W
authors.initials: GW
authors.lastname: Laver
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D011487:Protein Conformation
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D009439:Neuraminidase