title: Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.
abstract: Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom. simon.jf.macdonald@gsk.com
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.forename: Keith G
authors.initials: KG
authors.lastname: Watson
authors.forename: Rachel
authors.initials: R
authors.lastname: Cameron
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Derek A
authors.initials: DA
authors.lastname: Demaine
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Fenton
authors.forename: David
authors.initials: D
authors.lastname: Gower
authors.forename: J Nicole
authors.initials: JN
authors.lastname: Hamblin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hamilton
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Hart
authors.forename: Graham G A
authors.initials: GG
authors.lastname: Inglis
authors.forename: Betty
authors.initials: B
authors.lastname: Jin
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Jones
authors.forename: Darryl B
authors.initials: DB
authors.lastname: McConnell
authors.forename: Andy M
authors.initials: AM
authors.lastname: Mason
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Owens
authors.forename: Nigel
authors.initials: N
authors.lastname: Parry
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Reece
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Shanahan
authors.forename: Donna
authors.initials: D
authors.lastname: Smith
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Wu
authors.forename: Simon P
authors.initials: SP
authors.lastname: Tucker
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002850:Chromatography, Gel; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines; D007202:Indicators and Reagents; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011714:Pyrans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D053243:Zanamivir
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D007202:Indicators and Reagents; D011714:Pyrans; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir