GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein.
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.
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Margaret J
MJ
Clark
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.
Chandra
C
Miduturu
Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Aaron G
AG
Schmidt
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Xuling
X
Zhu
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Jared D
JD
Pitts
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.
Jinhua
J
Wang
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Supanee
S
Potisopon
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.
Jianming
J
Zhang
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.
Amy
A
Wojciechowski
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Justin Jang
JJ
Hann Chu
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.
Nathanael S
NS
Gray
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: priscilla_yang@hms.harvard.edu.
Priscilla L
PL
Yang
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D000998:Antiviral Agents; C000589763:E-glycoprotein, Dengue virus type 1; C051821:E-glycoprotein, Dengue virus type 2; C000589764:E-glycoprotein, Dengue virus type 3; C508526:GNF-2 compound; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014759:Viral Envelope Proteins; C466981:glycoprotein E, dengue virus type 4; D016315:Proto-Oncogene Proteins c-abl