GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein

Cell Chem Biol. 2016 Apr 21;23(4):443-52. doi: 10.1016/j.chembiol.2016.03.010.


Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the pre-fusion conformation that exists on the virion surface, and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides "lead" compounds for further optimization efforts.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dengue Virus / drug effects*
  • Dengue Virus / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Structure
  • NIH 3T3 Cells
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / deficiency
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Viral Envelope Proteins / antagonists & inhibitors
  • Viral Envelope Proteins / metabolism


  • Antiviral Agents
  • E-glycoprotein, Dengue virus type 1
  • E-glycoprotein, Dengue virus type 2
  • E-glycoprotein, Dengue virus type 3
  • GNF-2 compound
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Viral Envelope Proteins
  • glycoprotein E, dengue virus type 4
  • Proto-Oncogene Proteins c-abl