title: Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses.
abstract: The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti-influenza drug. However, oseltamivir-resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir-resistant, alternative therapy options are needed. Herein, we show that a structure-based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir-resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild-type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir-resistance mutation itself caused susceptibility to these drugs.
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Bindumadhav
authors.initials: B
authors.lastname: Marathe
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. jzheng@jsei.ucla.edu.|Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. jzheng@jsei.ucla.edu.|Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. jzheng@jsei.ucla.edu.
authors.forename: Jie J
authors.identifier: http://orcid.org/0000-0001-6524-6800
authors.initials: JJ
authors.lastname: Zheng
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D053139:Oseltamivir / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir
keywords: computational chemistry; drug discovery; drug repurposing; influenza viruses; neuraminidase
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