Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication

Virology. 2006 Sep 30;353(2):294-306. doi: 10.1016/j.virol.2006.05.028. Epub 2006 Jul 3.

Abstract

All coronaviruses encode a small hydrophobic envelope (E) protein, which mediates viral assembly and morphogenesis by an unknown mechanism. We have previously shown that the E protein from Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) forms cation-selective ion channels in planar lipid bilayers (Wilson, L., McKinlay, C., Gage, P., Ewart, G., 2004. SARS coronavirus E protein forms cation-selective ion channels. Virology 330(1), 322-331). We now report that three other E proteins also form cation-selective ion channels. These E proteins were from coronaviruses representative of taxonomic groups 1-3: human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and infectious bronchitis virus (IBV), respectively. It appears, therefore, that coronavirus E proteins in general, belong to the virus ion channels family. Hexamethylene amiloride (HMA)--an inhibitor of the HIV-1 Vpu virus ion channel--inhibited the HCoV-229E and MHV E protein ion channel conductance in bilayers and also inhibited replication of the parent coronaviruses in cultured cells, as determined by plaque assay. Conversely, HMA had no antiviral effect on a recombinant MHV with the entire coding region of E protein deleted (MHVDeltaE). Taken together, the data provide evidence of a link between inhibition of E protein ion channel activity and the antiviral activity of HMA.

MeSH terms

  • Amiloride / analogs & derivatives*
  • Amiloride / pharmacology
  • Amino Acid Sequence
  • Animals
  • Antiviral Agents / pharmacology
  • Cell Line
  • Coronavirus / genetics
  • Coronavirus / physiology*
  • Humans
  • Ion Channel Gating
  • Ion Channels / antagonists & inhibitors*
  • Mice
  • Molecular Sequence Data
  • Sodium Channel Blockers / pharmacology*
  • Viral Envelope Proteins / antagonists & inhibitors*
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Ion Channels
  • Sodium Channel Blockers
  • Viral Envelope Proteins
  • 5-(N,N-hexamethylene)amiloride
  • Amiloride