Tags

Type your tag names separated by a space and hit enter

In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675.

Abstract

With the recent introduction of neuraminidase (NA) inhibitors into clinical practice for the treatment of influenza virus infections, considerable attention has been focused on the potential for resistance development and cross-resistance between different agents from this class. A-315675 is a novel influenza virus NA inhibitor that has potent enzyme activity and is highly active in cell culture against a variety of strains of influenza A and B viruses. To further assess the therapeutic potential of this compound, in vitro resistance studies have been conducted and a comparative assessment has been made relative to oseltamivir carboxylate. The development of viral resistance to A-315675 was studied by in vitro serial passage of influenza A/N9 virus strains grown in MDCK cells in the presence of increasing concentrations of A-315675. Parallel passaging experiments were conducted with oseltamivir carboxylate, the active form of a currently marketed oral agent for the treatment of influenza virus infections. Passage experiments with A-315675 identified a variant at passage 8 that was 60-fold less susceptible to the compound. Sequencing of the viral population identified an E119D mutation in the NA gene, but no mutations were observed in the hemagglutinin (HA) gene. However, by passage 10 (2.56 microM A-315675), two mutations (R233K, S339P) in the HA gene appeared in addition to the E119D mutation in the NA gene, resulting in a 310-fold-lower susceptibility to A-315675. Further passaging at higher drug concentrations had no effect on the generation of further NA or HA mutations (20.5 microM A-315675). This P15 virus displayed 355-fold-lower susceptibility to A-315675 and >175-fold-lower susceptibility to zanamivir than did wild-type virus, but it retained a high degree of susceptibility to oseltamivir carboxylate. By comparison, virus variants recovered from passaging against oseltamivir carboxylate (passage 14) harbored an E119V mutation and displayed a 6,000-fold-lower susceptibility to oseltamivir carboxylate and a 175-fold-lower susceptibility to zanamivir than did wild-type virus. Interestingly, this mutant still retained susceptibility to A-315675 (42-fold loss). This suggests that cross-resistance between A-315675- and oseltamivir carboxylate-selected variants in vitro is minimal.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • FREE Publisher Full Text
  • Authors+Show Affiliations

    ,

    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. m.molla@abbott.com

    , , , , , , , , , , ,

    Source

    Journal of virology 76:11 2002 Jun pg 5380-6

    MeSH

    Acetamides
    Animals
    Antiviral Agents
    Cell Line
    Dogs
    Drug Resistance, Viral
    Enzyme Inhibitors
    Genetic Variation
    Guanidines
    Hemagglutinin Glycoproteins, Influenza Virus
    Humans
    Influenza A virus
    Mutagenesis
    Neuraminidase
    Oseltamivir
    Phenotype
    Pyrans
    Pyrrolidines
    Sialic Acids
    Zanamivir

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    11991966

    Citation

    Molla, Akhteruzzaman, et al. "In Vitro Selection and Characterization of Influenza a (A/N9) Virus Variants Resistant to a Novel Neuraminidase Inhibitor, A-315675." Journal of Virology, vol. 76, no. 11, 2002, pp. 5380-6.
    Molla A, Kati W, Carrick R, et al. In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675. J Virol. 2002;76(11):5380-6.
    Molla, A., Kati, W., Carrick, R., Steffy, K., Shi, Y., Montgomery, D., ... Kohlbrenner, W. (2002). In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675. Journal of Virology, 76(11), pp. 5380-6.
    Molla A, et al. In Vitro Selection and Characterization of Influenza a (A/N9) Virus Variants Resistant to a Novel Neuraminidase Inhibitor, A-315675. J Virol. 2002;76(11):5380-6. PubMed PMID: 11991966.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675. AU - Molla,Akhteruzzaman, AU - Kati,Warren, AU - Carrick,Robert, AU - Steffy,Kevin, AU - Shi,Yan, AU - Montgomery,Debra, AU - Gusick,Nanette, AU - Stoll,Vincent S, AU - Stewart,Kent D, AU - Ng,Teresa I, AU - Maring,Clarence, AU - Kempf,Dale J, AU - Kohlbrenner,William, PY - 2002/5/7/pubmed PY - 2002/6/11/medline PY - 2002/5/7/entrez SP - 5380 EP - 6 JF - Journal of virology JO - J. Virol. VL - 76 IS - 11 N2 - With the recent introduction of neuraminidase (NA) inhibitors into clinical practice for the treatment of influenza virus infections, considerable attention has been focused on the potential for resistance development and cross-resistance between different agents from this class. A-315675 is a novel influenza virus NA inhibitor that has potent enzyme activity and is highly active in cell culture against a variety of strains of influenza A and B viruses. To further assess the therapeutic potential of this compound, in vitro resistance studies have been conducted and a comparative assessment has been made relative to oseltamivir carboxylate. The development of viral resistance to A-315675 was studied by in vitro serial passage of influenza A/N9 virus strains grown in MDCK cells in the presence of increasing concentrations of A-315675. Parallel passaging experiments were conducted with oseltamivir carboxylate, the active form of a currently marketed oral agent for the treatment of influenza virus infections. Passage experiments with A-315675 identified a variant at passage 8 that was 60-fold less susceptible to the compound. Sequencing of the viral population identified an E119D mutation in the NA gene, but no mutations were observed in the hemagglutinin (HA) gene. However, by passage 10 (2.56 microM A-315675), two mutations (R233K, S339P) in the HA gene appeared in addition to the E119D mutation in the NA gene, resulting in a 310-fold-lower susceptibility to A-315675. Further passaging at higher drug concentrations had no effect on the generation of further NA or HA mutations (20.5 microM A-315675). This P15 virus displayed 355-fold-lower susceptibility to A-315675 and >175-fold-lower susceptibility to zanamivir than did wild-type virus, but it retained a high degree of susceptibility to oseltamivir carboxylate. By comparison, virus variants recovered from passaging against oseltamivir carboxylate (passage 14) harbored an E119V mutation and displayed a 6,000-fold-lower susceptibility to oseltamivir carboxylate and a 175-fold-lower susceptibility to zanamivir than did wild-type virus. Interestingly, this mutant still retained susceptibility to A-315675 (42-fold loss). This suggests that cross-resistance between A-315675- and oseltamivir carboxylate-selected variants in vitro is minimal. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/11991966/In_vitro_selection_and_characterization_of_influenza_A__A/N9__virus_variants_resistant_to_a_novel_neuraminidase_inhibitor_A_315675_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=11991966 DB - PRIME DP - Unbound Medicine ER -