title: Mapping the Resistance Potential of Influenza's H+Channel against an Antiviral Blocker.
abstract: The development of drug resistance has long plagued our efforts to curtail viral infections in general and influenza in particular. The problem is particularly challenging since the exact mode of resistance may be difficult to predict, without waiting for untreatable strains to evolve. Herein, a different approach is taken. Using a novel genetic screen, we map the resistance options of influenza's M2 channel against its aminoadamantane antiviral inhibitors. In the process, we could identify clinically known resistant mutations in a completely unbiased manner. Additionally, novel mutations were obtained, which, while known to exist in circulating viruses, were not previously classified as drug resistant. Finally, we demonstrated the approach against an anti-influenza drug that has not seen clinical use, identifying several resistance mutations in the process. In conclusion, we present and employ a method to predict the resistance options of influenza's M2 channel to antiviral agents ahead of clinical use and without medical hazard.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Assa
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Alhadeff
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 91904, Israel. Electronic address: arkin@cc.huji.ac.il.
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005820:Genetic Testing / Q000379:methods*; D005827:Genetics, Microbial / Q000379:methods; D008967:Molecular Biology / Q000379:methods; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D050505:Mutant Proteins; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: antiviral; channel blocker; drug resistance; influenza