title: Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors.
abstract: The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, <10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp-->Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.
authors.affiliation: Division of Infectious Diseases and International Health, Department of Internal Medicine, University of Virginia Health Sciences Center, P.O. Box 800473, 1300 Jefferson Ave., Rm. 2231, Charlottesville, Virginia 22908, USA.
authors.forename: Vasiliy P
authors.initials: VP
authors.lastname: Mishin
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hayden
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Gubareva
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D020134:Catalytic Domain; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005289:Ferrets; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase