title: Neuraminidase mutations conferring resistance to laninamivir lead to faster drug binding and dissociation.
abstract: The neuraminidase (NA) inhibitors oseltamivir and zanamivir are administered twice daily for 5days for treatment of influenza. Laninamivir is a 7-methoxy derivative of zanamivir, but a single dose is effective when taken as the laninamivir octanoate prodrug. We show here in IC50 kinetics assays and a solid phase reactivation assay that compared to zanamivir laninamivir also demonstrates slow binding to but slower dissociation from multiple wild type NAs. A D197E mutation in an influenza B and an E119G in an N9 neuraminidase which confer 15- and 150-fold resistance to laninamivir result in faster binding and dissociation. Despite similar IC50s our assays demonstrate more rapid dissociation of laninamivir from clade 1 compared to 2 H5N1 NAs.
authors.affiliation: CSIRO Manufacturing, 343 Royal Parade, Parkville, 3052, Australia. Electronic address: mck245@csiro.au.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McKimm-Breschkin
authors.affiliation: CSIRO Manufacturing, 343 Royal Parade, Parkville, 3052, Australia. Electronic address: susan.barrett@csiro.au.
authors.forename: Susan
authors.initials: S
authors.lastname: Barrett
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D006146:Guanidines; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D009981:Influenza B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics* / Q000378:metabolism*; D053139:Oseltamivir / Q000378:metabolism / Q000494:pharmacology; D011714:Pyrans; D012794:Sialic Acids; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D014764:Viral Proteins; D053139:Oseltamivir; C546918:laninamivir; C487630:NA protein, influenza A virus; C541223:NA protein, influenza B virus; D009439:Neuraminidase; D053243:Zanamivir
keywords: Enzyme kinetics; Influenza; Laninamivir; Resistance