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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Clark MJ,Miduturu C,Schmidt AG,Zhu X,Pitts JD,Wang J,Potisopon S,Zhang J,Wojciechowski A,Hann Chu JJ,Gray NS,Yang PLdoi
10.1016/j.chembiol.2016.03.010subject
Has Abstractpub_date
2016-04-21 00:00:00pages
443-52issue
4eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30088-5journal_volume
23pub_type
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