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

BOLLINI, MARIELA; BATTINI, LEANDRO; ÁLVAREZ, DIEGO E

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

INSTITUTO DE LA QUÍMICA Y METABOLISMO DEL FÁRMACO (IQUIMEFA - CONICET)

Chikungunya virus belongs to the alphavirus genus of the Togaviridae family. It is transmitted by mosquitoes of theAedes species and it is the causing agent of chikungunya fever, a neglected viral disease that has reemerged in recentyears [1] . Until today, no antiviral agent or vaccine has been approved for treatment or prevention of chikungunyainfection. Hence, there is an urgent need for the development of potent and safe antivirals towards the virus [2] .Chikungunya virus particles are composed of heterodimers of E1 and E2 transmembrane proteins, a host derivedlipid bilayer, and the nucleocapsid (NC) associated to a single copy of the RNA genome [3] . Functionally, E1 and E2are essential for the viral adsorption and entry into the host cell, and the heterodimer has recently been crystalized[4]. In this context, with the aim of identifying antiviral compounds against chikungunya virus that prevent viral entryinto the host cell, an in silico structure-based virtual screening targeting the E1-E2 heterodimer was performed.Possible binding pockets within the heterodimer were detected using geometric algorithms and were inagreement with those reported in literature [5] . Pocket A was selected based on the druggability score and its biologicalsignificance. Around 80000 compounds from the Maybridge and Chembridge databases were docked into the pocketon two crystal structures of the protein using Autodock Vina (PDB IDs: 3n40 y 3n42). The top scored molecules werefiltered by their ADMET and PAINS properties and by visual inspection. Eight selected compounds were bought orsynthesized and tested for their cytotoxicity and antiviral activity using a recombinant CHIKV-GFP reporter assay. Oneof the assayed compounds turned out to be a hit, with an EC50 value of 11 μM.Twenty five derivatives were synthesized and assayed, resulting in several compounds with improved antiviral activity.Compound 2 (EC 50 = 1.5 μM) was chosen to study the mechanism of action. Time of drug addition assays showed thatthe compound exerts its antiviral activity in the early stages of the viral life cycle. Additionally, the compound inhibitedviral entry into the host cell but had no effect on viral adsorption. Both results are in agreement with the proposedtarget and with our initial hypothesis. In conclusion, we were able to identify novel antiviral compounds that inhibitchikungunya virus entry into the host cell following a structure based virtual screening approach.