3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus

PLoS One. 2014 Oct 10;9(10):e110089. doi: 10.1371/journal.pone.0110089. eCollection 2014.

Abstract

Infections by influenza A viruses (IAV) are a major health burden to mankind. The current antiviral arsenal against IAV is limited and novel drugs are urgently required. Medicinal plants are known as an abundant source for bioactive compounds, including antiviral agents. The aim of the present study was to characterize the anti-IAV potential of a proanthocyanidin-enriched extract derived from the aerial parts of Rumex acetosa (RA), and to identify active compounds of RA, their mode of action, and structural features conferring anti-IAV activity. In a modified MTT (MTTIAV) assay, RA was shown to inhibit growth of the IAV strain PR8 (H1N1) and a clinical isolate of IAV(H1N1)pdm09 with a half-maximal inhibitory concentration (IC50) of 2.5 µg/mL and 2.2 µg/mL, and a selectivity index (SI) (half-maximal cytotoxic concentration (CC50)/IC50)) of 32 and 36, respectively. At RA concentrations>1 µg/mL plaque formation of IAV(H1N1)pdm09 was abrogated. RA was also active against an oseltamivir-resistant isolate of IAV(H1N1)pdm09. TNF-α and EGF-induced signal transduction in A549 cells was not affected by RA. The dimeric proanthocyanidin epicatechin-3-O-gallate-(4β→8)-epicatechin-3'-O-gallate (procyanidin B2-di-gallate) was identified as the main active principle of RA (IC50 approx. 15 µM, SI≥13). RA and procyanidin B2-di-gallate blocked attachment of IAV and interfered with viral penetration at higher concentrations. Galloylation of the procyanidin core structure was shown to be a prerequisite for anti-IAV activity; o-trihydroxylation in the B-ring increased the anti-IAV activity. In silico docking studies indicated that procyanidin B2-di-gallate is able to interact with the receptor binding site of IAV(H1N1)pdm09 hemagglutinin (HA). In conclusion, the proanthocyanidin-enriched extract RA and its main active constituent procyanidin B2-di-gallate protect cells from IAV infection by inhibiting viral entry into the host cell. RA and procyanidin B2-di-gallate appear to be a promising expansion of the currently available anti-influenza agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Biflavonoids / chemistry
  • Biflavonoids / pharmacology*
  • Binding Sites
  • Catechin / chemistry
  • Catechin / pharmacology*
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • Cytopathogenic Effect, Viral
  • Dogs
  • Epidermal Growth Factor / pharmacology
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Humans
  • Influenza A virus / drug effects*
  • Influenza A virus / physiology*
  • Models, Molecular
  • Molecular Conformation
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*
  • Proanthocyanidins / chemistry
  • Proanthocyanidins / pharmacology*
  • Protein Binding
  • Rumex / chemistry*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / pharmacology
  • Virus Attachment / drug effects*

Substances

  • Antiviral Agents
  • Biflavonoids
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Plant Extracts
  • Proanthocyanidins
  • Tumor Necrosis Factor-alpha
  • proanthocyanidin
  • procyanidin
  • Epidermal Growth Factor
  • Catechin

Grants and funding

The authors acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publication Fund of University of Muenster. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.