Mapping the Resistance Potential of Influenza's H+ Channel against an Antiviral Blocker

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 dif...

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Bibliographic Details
Published in:Journal of molecular biology 2016-10, Vol.428 (20), p.4209-4217
Main Authors: Assa, Dror, Alhadeff, Raphael, Krugliak, Miriam, Arkin, Isaiah T.
Format: Article
Language:English
Subjects:
Amantadine - pharmacology
antiviral
Antiviral Agents - pharmacology
channel blocker
drug resistance
Drug Resistance, Viral
Genetic Testing - methods
Genetics, Microbial - methods
influenza
Molecular Biology - methods
Mutant Proteins - genetics
Mutant Proteins - metabolism
Orthomyxoviridae - drug effects
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Viral Matrix Proteins - genetics
Viral Matrix Proteins - metabolism
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Summary: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. [Display omitted] •Viruses are a serious threat due to their ability to constantly mutate and develop resistance to medical treatment.•A genetic screen is developed to exhaustively map the resistance options of a virus against an antiviral drug.•When applied to drugs that inhibit influenza by blocking its H+ channel, we were able to obtain known clinical resistance mutations.•We provide an approach, which is ahead of any clinical use, to determine how influenza will develop resistance against antiviral drugs that block its H+ channel.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2016.08.007