CIBION   24492
CENTRO DE INVESTIGACIONES EN BIONANOCIENCIAS "ELIZABETH JARES ERIJMAN"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Dual structure-based approach towards the design of inhibitors of the Dengue virus envelope protein
Autor/es:
GEBHARD, LEOPOLDO G.; CAVASOTTO, CLAUDIO N.; EMILSE S. LEAL; GABRIELA AUCAR; MARÍA JOSÉ PASCUAL; . MARIELA BOLLINI; ANDREA V. GAMARNIK
Lugar:
Munich
Reunión:
Congreso; 11th Triennial Congress of the World Association of Theoretical and Computational Chemists (WATOC); 2017
Resumen:
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 many popular tourist destinations in Latin America, Southeast Asia and the Pacific islands.1 However, no clinically approved antiviral therapy is available. The first dengue vaccine has been recently approved and licensed in six countries, but it was reported to be 60% effective and not to generate immunity against all serotypes reported. To satisfy this unmet medical need for an antiviral therapy, both industry and academia have taken multiple approaches to develope anti dengue virus agents. Entry of the dengue virus into a host cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobic pocket occupied by the detergent n-octyl-β-D-glucoside (β-OG) lying at a hinge region between domains I and II. 2 Therefore, the E protein is an attractive target for the development of antiviral agents. We used in silico structure-based virtual screening and de novo design approaches to identify small-molecules that likely bind to the β-OG binding site. Twenty-three structurally different compounds were selected from docking-based virtual screening and ten compounds emerging from de novo design were synthesized. The antiviral activity of the compounds was evaluated using an assay based on a luciferase-expressing dengue reporter virus. Six compounds showed antiviral activity in the 3-10 μM range and displayed a good therapeutic index. Based on their antiviral potency and selectivity, these compounds will be subject of a more detailed and elaborate virological study to gain insights into the precise molecular mechanism of action.