Inhibitors of flavivirus by targeting the NS2B‐NS3 protease interface

Abstract

Flaviviruses require the activity of their viral protease in order to process the single polyprotein encoded by their genome into individual proteins and assemble an infectious virion. This protease consists of a large catalytic subunit (NS3) and a smaller accessory subunit (NS2B) important for function. Using the previously solved flavivirus protease crystal structures, we identified three putative sites of interaction between NS2B and NS3 which we then queried with a virtual screen of NCI library compounds, followed by subsequent in vitro biochemical screening of the resultant candidates. Of more than one hundred initial candidate compounds that passed the virtual screen, thirty‐six demonstrated significant inhibition in vitro. Three most potent compounds, 227186, 73101, and 65828 were further investigated and found to significantly reduce titers of Dengue virus 2 on A549 cells.Support or Funding InformationAI133219, AI134568, AI131669This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.