DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL ANTIVIRALS TOWARDS CHIKUNGUNYA VIRUS

DIEGO E. ALVAREZ; LEANDRO BATTINI; MARIELA BOLLINI

Buenos Aires

Congreso; Drug Discovery for Neglected Tropical Diseases Congress 2018; 2018

Chikungunya fever is a neglected viral disease caused by the infection with chikungunya virus (CHIKV). It is transmitted by mosquitoes of the Aedes genus and characterized by severe polyarthralgia that may last for months. Until today, no antiviral agent or vaccine has been approved for treatment or prevention of CHIKV infection, hence, there is an urgent need for the development of antivirals towards this virus. In this context, we performed a structure-based virtual screening targeting the envelope glycoprotein heterodimer E1-E2 exposed on the surface of the virus particle. E2 and E1 mediate receptor recognition and fusion of virus and cell membranes, respectively. Therefore, our hypothesis was that inhibiting the function of this heterodimer may prevent the entry of the viral particle into the host cell. To achieve our goal, we first identified possible binding pockets within E1-E2 and then performed a virtual screening of commercially available compound databases (Maybridge and Chembridge) using Autodock Vina. Selected compounds were bought or synthesized and then tested against CHIKV using a reporter virus assay. Further characterization of the mechanism of action of one of the active compounds showed block of virus entry. Moreover, selection and sequence analysis of drug-resistant mutants identified aminoacid changes which indicate that compound-protein interactions occurred at the proposed binding pocket.