In vitro evaluation of synergistic inhibitory effects of neuraminidase inhibitors and methylglyoxal against influenza virus infection

Arch Med Res. 2015 Jan;46(1):8-16. doi: 10.1016/j.arcmed.2014.12.002. Epub 2014 Dec 15.


Background and aims: Influenza virus infections are serious public health concerns worldwide that cause considerable mortality and morbidity. Moreover, the emergence of resistance to anti-influenza viral agents underscores the need to develop new anti-influenza viral agents and novel treatment strategies. Recently, we identified anti-influenza viral activity of manuka honey. Therefore, we hypothesized that methylglyoxal (MGO), a key component of manuka honey, may impart anti-influenza viral activity. The aim of this study was to evaluate the anti-influenza viral activity of MGO and its potential in combination treatments with neuraminidase (NA) inhibitors.

Methods: MDCK cells were used to evaluate anti-influenza viral activity. To evaluate the mechanism of MGO, plaque inhibition assays were performed. The synergistic effects of MGO and viral NA inhibitors were tested.

Results: MGO inhibited influenza virus A/WSN/33 replication 50% inhibitory concentration = 240 ± 190 μM; 50% cytotoxic concentration = 1.4 ± 0.4 mM; selective index (SI) = 5.8, which is related to its virucidal effects. Moreover, we found that MGO showed promising activity against various influenza strains. A synergistic effect was observed by a marked increase in SI of NA inhibitors at ∼1/100(th) of their single usage. A synergistic effect of MGO and oseltamivir was also observed against oseltamivir-resistant virus.

Conclusions: Our results showed that MGO has potent inhibitory activity against influenza viruses and also enhanced the effect of NA inhibitors. Thus, the co-administration of MGO and NA inhibitors should be considered for treatment of influenza virus infections.

Keywords: Anti-influenza viral drug; Influenza virus; Manuka honey; Methylglyoxal; Neuraminidase inhibitors; Synergistic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Dogs
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors / pharmacology
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H3N2 Subtype / drug effects
  • Influenza A Virus, H5N2 Subtype / drug effects
  • Influenza A virus / drug effects*
  • Inhibitory Concentration 50
  • Madin Darby Canine Kidney Cells
  • Neuraminidase / antagonists & inhibitors*
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / virology
  • Oseltamivir / pharmacology*
  • Pyruvaldehyde / pharmacology*
  • Virus Replication / drug effects


  • Antiviral Agents
  • Enzyme Inhibitors
  • Oseltamivir
  • Pyruvaldehyde
  • Neuraminidase