Broad-spectrum antiviral agents: secreted phospholipase A 2 targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane

Sci Rep. 2017 Nov 21;7(1):15931. doi: 10.1038/s41598-017-16130-w.

Abstract

Hepatitis C virus (HCV), dengue virus (DENV) and Japanese encephalitis virus (JEV) belong to the family Flaviviridae. Their viral particles have the envelope composed of viral proteins and a lipid bilayer acquired from budding through the endoplasmic reticulum (ER). The phospholipid content of the ER membrane differs from that of the plasma membrane (PM). The phospholipase A2 (PLA2) superfamily consists of a large number of members that specifically catalyse the hydrolysis of phospholipids at a particular position. Here we show that the CM-II isoform of secreted PLA2 obtained from Naja mossambica mossambica snake venom (CM-II-sPLA2) possesses potent virucidal (neutralising) activity against HCV, DENV and JEV, with 50% inhibitory concentrations (IC50) of 0.036, 0.31 and 1.34 ng/ml, respectively. In contrast, the IC50 values of CM-II-sPLA2 against viruses that bud through the PM (Sindbis virus, influenza virus and Sendai virus) or trans-Golgi network (TGN) (herpes simplex virus) were >10,000 ng/ml. Moreover, the 50% cytotoxic (CC50) and haemolytic (HC50) concentrations of CM-II-sPLA2 were >10,000 ng/ml, implying that CM-II-sPLA2 did not significantly damage the PM. These results suggest that CM-II-sPLA2 and its derivatives are good candidates for the development of broad-spectrum antiviral drugs that target viral envelope lipid bilayers derived from the ER membrane.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Cattle
  • Cell Death / drug effects
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Hemolysis / drug effects
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism*
  • Isoenzymes / metabolism
  • Lipid Bilayers / metabolism*
  • Membrane Lipids / metabolism*
  • Phospholipases A2, Secretory / pharmacology*
  • Swine
  • Terpenes / pharmacology
  • Virus Internalization / drug effects
  • Virus Replication / drug effects
  • Viruses / drug effects

Substances

  • Antiviral Agents
  • Isoenzymes
  • Lipid Bilayers
  • Membrane Lipids
  • Terpenes
  • viral envelope lipids
  • manoalide
  • Phospholipases A2, Secretory