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Basic Characteristics of Mutations
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Mutation Site
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S31N |
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Mutation Site Sentence
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Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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M2 |
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Standardized Encoding Gene
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M
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Genotype/Subtype
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H1N1;B/Victoria |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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Cell line
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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amantadine |
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Location
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- |
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Literature Information
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PMID
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28477572
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Title
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Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus
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Author
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Tonelli M,Naesens L,Gazzarrini S,Santucci M,Cichero E,Tasso B,Moroni A,Costi MP,Loddo R
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Journal
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European journal of medicinal chemistry
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Journal Info
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2017 Jul 28;135:467-478
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Abstract
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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC(50) = 0.060 muM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC(50) approximately 0.008 muM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC(50) = 5.8 muM, SI > 43).
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Sequence Data
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-
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