title: Difluorosialic acids, potent novel influenza virus neuraminidase inhibitors, induce fewer drug resistance-associated neuraminidase mutations than does oseltamivir.
abstract: Neuraminidase inhibitors (NAIs), including the most frequently prescribed oral therapeutic oseltamivir, play a critical role in the control of severe influenza virus (IFV) infections. However, recent reports of spread of an oseltamivir-resistant H1N1 pandemic strain in individuals who have never been exposed to oseltamivir highlight an urgent need for new antivirals against NAI-resistant IFVs. Difluorosialic acids (DFSAs) are a novel class of anti-IFV NAIs designed based on the mechanism of action of IFV NA, and distinguished by their covalent inhibition mode and their high structural similarity to the natural substrate, sialic acid. These characteristics should render the development of resistance a less rapid process. In this report, we evaluated the relative propensity of influenza A virus (IFV-A) NA to develop resistance against the DFSA class of inhibitor by passaging IFV-A strains in vitro in the presence of either oseltamivir or a representative DFSA (FeqGuDFSA). All the passage-selected lines gained mutations in hemagglutinin. Among the 12 oseltamivir-resistant passaged lines, five gained NA mutations and four of these were the well-defined H275Y mutation that causes oseltamivir resistance. In contrast, out of 15 DFSA-passaged lines, only 2 lines gained NA mutations. Further, NA inhibition assays indicated that these mutations did not change the sensitivity of NA to DFSA and thus the resistance to DFSA was not conferred by these NA mutations. These results strongly suggest that, compared to oseltamivir, IFV is less prone to development of resistance against DFSAs through NA mutations.
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: S-H Sheldon
authors.initials: SH
authors.lastname: Tai
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Agafitei
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Zhizeng
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Centre for Drug Research and Development (CDRD), 2259 Lower Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Liggins
authors.affiliation: British Columbia Centre for Disease Control, 655 West 12th Avenue, Vancouver, British Columbia V5Z 4R4, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Petric
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada. Electronic address: niikura@sfu.ca.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Niikura
mesh_terms: D000818:Animals; D004285:Dogs; D024882:Drug Resistance, Viral; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir / Q000494:pharmacology*; D012641:Selection, Genetic; D012692:Serial Passage; D012794:Sialic Acids / Q000494:pharmacology*; D014776:Virus Cultivation
chemical_list: D012794:Sialic Acids; D053139:Oseltamivir; D009439:Neuraminidase
keywords: DFSA; Difluorosialic acid; Drug resistance; Influenza virus; Neuraminidase inhibitor