Article
Inhibition profile of an orally bioavailable 5-amidino analog of oseltamivir in the influenza virus N1 background
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Authors
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Anja Hoffmann
- Department of Virology and Antiviral Therapy, Jena University Hospital, Jena
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Dennis Schade
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund
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Johannes Kirchmair
- Center for Bioinformatics, University of Hamburg, Hamburg
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Bernd Clement
- Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts University of Kiel, Kiel
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Andreas Sauerbrei
- Department of Virology and Antiviral Therapy, Jena University Hospital, Jena
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Michaela Schmidtke
- Department of Virology and Antiviral Therapy, Jena University Hospital, Jena
| Published: | September 30, 2016 |
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Outline
Text
Emergence of neuraminidase (NA) inhibitor (NAI) resistance is known to reduce the efficacy of influenza treatment. Recently, a 5-amidino analog of oseltamivir, (3R,4R,5S)-4-acetamido-5-(ethanimidoylamino)-3-(pentan-3-yloxy)-1-cyclohex-1-ene-1-carboxylic acid (5-amidino analog), was developed as novel orally bioavailable NAI inhibiting an oseltamivir-resistant seasonal H1N1 influenza A virus strain carrying H274Y [1]. Here, its inhibition profile was studied in a uniform genetic background by using influenza virus A/WSN/33 (WSN/33) variants with potentially resistance-conferring single N1 amino acid substitutions.
Because resistance to the sole approved, orally bioavailable NAI, oseltamivir, is mostly based on H274Y or N294S substitution in N1 [2], these two amino acid substitutions were introduced into the NA of WSN/33 via reverse genetics. Further introduced NAI resistance-conferring substitutions include Q136L and Y155H that were sporadically detected in NAI-resistant clinical isolates. In addition, WSN/33 variants with I427Q/M were generated which might affect NAI interaction with the arginine triade. As expected, NA enzymatic and/or replicative kinetics of rescued viruses were hampered. Apart from the 5-amidino analog of oseltamivir, the inhibition profiles of oseltamivir, a 5-guanidino analog of it [3], zanamivir, and a 4-amidino analog of zanamivir [4] were comparatively determined with the established set of six WSN/33 variants in NA inhibition assays. NAI susceptibility was only marginally affected by the Q136L and I427M substitutions. Beyond Y155H, the so far unreported substitution I427Q was shown to confer cross-resistance to NAIs. Oseltamivir resistance based on H274Y and N294S substitution was considerably reduced by its amidine and guanidine analogs.
Thus, the inhibition profile of the 5-amidino analog was improved compared to its parent drug.
References
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