Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin ?/?1 Heterodimer.

ABSTRACT: Dengue virus (DENV) threatens almost 70% of the world's population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) ?/?1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5?IMP?/?1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMP? binding to IMP?1, but can dissociate preformed IMP?/?1 heterodimer, through targeting the IMP? armadillo (ARM) repeat domain to impact IMP? thermal stability and ?-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics.

SUBMITTER: Yang SNY 

PROVIDER: S-EPMC6468590 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature