tetano
Editor, Senior Moderator
Mol Pharmacol. 2016 Jul 6. pii: mol.116.105346. [Epub ahead of print]
[h=1]Pharmacological characterizations of the spectrum of antiviral activity and genetic barrier of drug resistance of M2-S31N channel blockers.[/h] Ma C[SUP]1[/SUP], Zhang J[SUP]1[/SUP], Wang J[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Adamantanes, amantadine and rimantadine, are one of the two classes of FDA-approved antiviral drugs used for the prevention and treatment of influenza A virus infections. They inhibit viral replication by blocking the wild-type (WT) M2 proton channel, thus preventing viral uncoating. However, their use was discontinued due to widespread drug resistance. Among a handful of drug-resistant mutants, M2-S31N is the predominant mutation and persists in more than 95% of currently circulating influenza A strains. We recently designed two classes of M2-S31N inhibitors, S31N-specific inhibitors and S31N/WT dual inhibitors, which are represented by WJ379 and BC035 respectively. However, their antiviral activities against currently circulating influenza A viruses and their genetic barrier to drug resistance are unknown. In this report, we evaluated the therapeutic potential of these two classes of M2-S31N inhibitors (WJ379 and BC035) by profiling their antiviral efficacy against multidrug-resistant influenza A viruses, in vitro drug resistance barrier, and synergistic effect with oseltamivir. We found that M2-S31N inhibitors were active against several influenza A viruses that are resistant to one or both classes of FDA-approved anti-influenza drugs. In addition, M2-S31N inhibitors display a higher in vitro genetic barrier to drug resistance than amantadine. The antiviral effect of WJ379 was also synergistic with oseltamivir carboxylate. Overall, these results reaffirm that M2-S31N inhibitors are promising antiviral drug candidates that warrant further development.
The American Society for Pharmacology and Experimental Therapeutics.
[h=4]KEYWORDS:[/h] Antiviral drugs; Ion channel regulation
PMID: 27385729 DOI: 10.1124/mol.116.105346
[PubMed - as supplied by publisher]
[h=1]Pharmacological characterizations of the spectrum of antiviral activity and genetic barrier of drug resistance of M2-S31N channel blockers.[/h] Ma C[SUP]1[/SUP], Zhang J[SUP]1[/SUP], Wang J[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Adamantanes, amantadine and rimantadine, are one of the two classes of FDA-approved antiviral drugs used for the prevention and treatment of influenza A virus infections. They inhibit viral replication by blocking the wild-type (WT) M2 proton channel, thus preventing viral uncoating. However, their use was discontinued due to widespread drug resistance. Among a handful of drug-resistant mutants, M2-S31N is the predominant mutation and persists in more than 95% of currently circulating influenza A strains. We recently designed two classes of M2-S31N inhibitors, S31N-specific inhibitors and S31N/WT dual inhibitors, which are represented by WJ379 and BC035 respectively. However, their antiviral activities against currently circulating influenza A viruses and their genetic barrier to drug resistance are unknown. In this report, we evaluated the therapeutic potential of these two classes of M2-S31N inhibitors (WJ379 and BC035) by profiling their antiviral efficacy against multidrug-resistant influenza A viruses, in vitro drug resistance barrier, and synergistic effect with oseltamivir. We found that M2-S31N inhibitors were active against several influenza A viruses that are resistant to one or both classes of FDA-approved anti-influenza drugs. In addition, M2-S31N inhibitors display a higher in vitro genetic barrier to drug resistance than amantadine. The antiviral effect of WJ379 was also synergistic with oseltamivir carboxylate. Overall, these results reaffirm that M2-S31N inhibitors are promising antiviral drug candidates that warrant further development.
The American Society for Pharmacology and Experimental Therapeutics.
[h=4]KEYWORDS:[/h] Antiviral drugs; Ion channel regulation
PMID: 27385729 DOI: 10.1124/mol.116.105346
[PubMed - as supplied by publisher]