Identification of Small-molecules Dengue Virus Entry Inhibitor

LEAL, EMILSE S.; IGLESIAS, NESTOR G.; AUCAR, MARÍA G.; GEBHARD, LEOPOLDO G.; CASAL, JUAN J.; VALDEZ, DAMIÁN; GAMARNIK, ANDREA V.; CAVASOTTO, CLAUDIO N.; BOLLINI, MARIELA

Conferencia; Frontiers in Bioscience 2; 2016

Dengue is a mosquito-borne viral disease that has become a major public health concern worldwide in recent years. At present, dengue is endemic in Argentina, and a Dengue fever outbreak has been registered in 13 out of the 24 Argentinean provinces in 2016. However, no clinically approved antiviral therapy is available. The first dengue vaccine has been recently approved and licensed in six countries, and it was reported to be 60% effective and not to generate immunity against all serotypes reported. To meet this unmet medical need for an antiviral therapy, industry and academia have taken multiples approaches to develope antiflavivirus agents. Entry of the virus into a host cell is mediated by its major envelope protein, E. The cristal structure of the E protein reveals a hydrophobic pocket BOG (β-N-octylglucoside) lying at a hinge region between domain I and II. Therefore, the E protein is an attractive target for the development of antiviral agents. We performed in silico virtual screening and de novo design approaches to identify compounds that likely bind BOG pocket. Twenty structurally different compounds were selected from virtual screening and ten compounds emerging from de novo design were synthesized. The antiviral activities of the compounds were evaluated using an assay based on a luciferase reporter virus. Seven compounds showed antiviral activity in the 1-10 μM range and displayed a good therapeutic index. Based on their antiviral potency and selectivity, these compounds will become the subject of more detailed and elaborate virological study to gain insights into the precise molecular mechanism of action.