Luteolin restricts dengue virus replication through inhibition of the proprotein convertase furin

Antiviral Res. 2017 Jul;143:176-185. doi: 10.1016/j.antiviral.2017.03.026. Epub 2017 Apr 5.

Abstract

In many countries afflicted with dengue fever, traditional medicines are widely used as panaceas for illness, and here we describe the systematic evaluation of a widely known natural product, luteolin, originating from the "heat clearing" class of herbs. We show that luteolin inhibits the replication of all four serotypes of dengue virus, but the selectivity of the inhibition was weak. In addition, ADE-mediated dengue virus infection of human cell lines and primary PBMCs was inhibited. In a time-of-drug-addition study, luteolin was found to reduce infectious virus particle formation, but not viral RNA synthesis, in Huh-7 cells. During the virus life cycle, the host protease furin cleaves the pr moiety from prM protein of immature virus particles in the trans-Golgi network to produce mature virions. Analysis of virus particles from luteolin-treated cells revealed that prM was not cleaved efficiently. Biochemical interrogation of human furin showed that luteolin inhibited the enzyme activity in an uncompetitive manner, with Ki value of 58.6 μM, suggesting that treatment may restrict the virion maturation process. Luteolin also exhibited in vivo antiviral activity in mice infected with DENV, causing reduced viremia. Given the mode of action of luteolin and its widespread source, it is possible that it can be tested in combination with other dengue virus inhibitors.

Keywords: Antiviral therapy; Dengue virus; Furin; Luteolin; Traditional Chinese medicine; Virus maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Cricetinae
  • DNA Replication / drug effects
  • Dengue / drug therapy
  • Dengue / virology
  • Dengue Virus / classification
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • Disease Models, Animal
  • Drugs, Chinese Herbal / pharmacology
  • Enzyme Activation / drug effects
  • Furin / metabolism*
  • HEK293 Cells
  • Humans
  • Kinetics
  • Luteolin / administration & dosage
  • Luteolin / antagonists & inhibitors*
  • Luteolin / chemistry
  • Male
  • Mice
  • Proprotein Convertases / drug effects*
  • Proprotein Convertases / metabolism
  • RNA, Viral / drug effects
  • Viremia / drug therapy
  • Virion / drug effects
  • Virus Replication / drug effects*
  • trans-Golgi Network / drug effects

Substances

  • Antiviral Agents
  • Drugs, Chinese Herbal
  • RNA, Viral
  • Proprotein Convertases
  • Furin
  • Luteolin