Pharmacological characterization of the spectrum of antiviral activity and genetic barrier to drug resistance of M2-S31N channel blockers

Chunlong Ma, Jiantao Zhang, Jun Wang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Adamantanes (amantadine and rimantadine) are one of the two classes of Food and Drug Administration- 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 N-[(5- cyclopropyl-1,2-oxazol-3-yl)methyl]adamantan-1- Amine (WJ379) and N-[(5-bromothiophen-2-yl)methyl]adamantan-1- Amine (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 Food and Drug Administration- 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.

Original languageEnglish (US)
Pages (from-to)188-198
Number of pages11
JournalMolecular Pharmacology
Volume90
Issue number3
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Drug Resistance
Antiviral Agents
Influenza A virus
Pharmacology
Amantadine
United States Food and Drug Administration
Human Influenza
Amines
Virus Uncoating
Rimantadine
Adamantane
Oseltamivir
Virus Diseases
Pharmaceutical Preparations
Protons
Mutation
In Vitro Techniques
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacological characterization of the spectrum of antiviral activity and genetic barrier to drug resistance of M2-S31N channel blockers. / Ma, Chunlong; Zhang, Jiantao; Wang, Jun.

In: Molecular Pharmacology, Vol. 90, No. 3, 01.09.2016, p. 188-198.

Research output: Contribution to journalArticle

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