Síntese e avaliação antiviral de potenciais inibidores baseados em fragmentos (FBDD) contra os vírus dengue e zika

Abstract

Dengue Virus (DENV) and Zika (ZIKV) belong to Flaviviridae family and are responsible for infecting more than 300 million people annually. These viruses share a significant genomic similarity to each other, making it possible to plan dual inhibitors against both. The structural envelope protein (E) is critical to mediating virus entry/fusion into the host cell; and the complex non-structural proteins NS2B-NS3, indispensable for the processing of the viral polyprotein during the replication cycle, as well as suppression of the host's immune response, new antiviral agents can be designed for such macromolecules. Aiming at potential inhibitors of such targets, we sought to develop a FBDD protocol via molecular docking to screen the best molecular fragments from an in-house library. Thus, 254 fragments were designed and optimized (AM1), followed by molecular docking (Gold®) and (AutoDock Vina®) against the aforementioned proteins. From the FBDD and adopting the values of 30 (FitScore) and -3.0 kcal/mol (affinity energy) as cutting criteria, 24 promising fragments were selected, composing a set of aldehydes and amines. Then, the most promising aldehyde, indole-3-carboxaldehyde, was selected for the synthesis of cyanoacrylamides and acrylates, yielding a set of 128 new molecules. Thus, two series of molecules were synthesized and evaluated against the serine protease NS2B-NS3 of ZIKV and DENV, in addition to cell assays. All compounds showed a non-cytotoxic profile and good solubility in biological media. In contrast, they did not show any antiviral activity in assays with infected cells. Finally, it is clear that structural modifications are needed to achieve antiviral activity, as well as to improve protease inhibition.