Structure-based design of novel inhibitors targeting the E protein from the Dengue virus

CAVASOTTO, CLAUDIO N.

Santos, SP

Congreso; XLII Congress of the Brazilian Biophysics Society; 2017

Dengue is a mosquito-borne viral disease that has become a major publichealth concern worldwide in recent years. However, no clinically approvedantiviral therapy is available. The first recently approved dengue vaccine hasbeen licensed in six countries, but it was reported to be 60% effective and notto generate immunity against all serotypes reported.  Thus, there is an unmet medical need for an alternativeantiviral therapy. Entry of the dengue virus into a host cell is mediated byits major envelope protein, E, whose crystalstructure reveals a hydrophobic pocket occupied by the detergentn-octyl-β-D-glucoside (β-OG) lying at a hinge region between domains I and II.Therefore, the E protein is anattractive target for the development of antiviral agents. We present a structure-baseddrug lead discovery approach to identify small-molecules targeting the β-OG bindingsite. More than twenty structurally different compounds were selected, and several of them showed antiviralactivity in the low micromolar range, exhibiting also good therapeutic indexes.Molecular dynamics simulations were performed to properly characterize theinteraction of some of these compounds with protein E and study the role of water molecule in mediating protein:ligandinteraction, paving the way for future ligand optimization enveavours.