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

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

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1
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, MA 02115, USA.
3
Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: priscilla_yang@hms.harvard.edu.

Abstract

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.

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