Dados do Trabalho

Título

Bis-naphthoquinones show promising in vitro and in silico Anti-ZIKV profile

Introdução

Zika virus (ZIKV), a mosquito-borne Flavivirus, has emerged as a significant global health threat. Currently, no vaccines or specific treatments exist for ZIKV.

Objetivo (s)

The aim of the present study was to investigate in vitro and in silico the potential antiviral properties of a series of 16 bis-naphthoquinones against a Brazilian ZIKV variant.

Material e Métodos

The compound's antiviral activity was verified against the Brazil-ZKV 2015 (GenBank: KU497555.1). Cytotoxicity was defined as the compound concentration capable of killing 50% of HEK-293 cells (CC50) after treatment with concentrations from 3.125 μM to 100 μM as verified by neutral red (NR), MTT and crystal violet (CV) staining assays. The concentration capable of inhibiting 50% of ZIKV production (EC50) was determined by the Reed Muench technique. Selectivity indexes (SI) were obtained as the CC50/EC50 ratio for each one of the investigated compounds. In-silico analysis was conducted to predict the compound's capability to target the ZIKV non-structural proteins NS3 and NS5. Molecular docking simulations were carried out using crystal structures of ZIKV protease, methyltransferase (5WZ2.PDB), and helicase (5MFX.PDB).

Resultados e Conclusão

Three bis-naphthoquinones (3g, 3h and 3i) showed low cytotoxicity to HEK-293 cells, allowing ZYKV antiviral activity investigation. EC50 were: 3g (EC50 2.8 ± 1.1); 3h (EC50 1.5 ± 1.0) and 3i (EC50 2.1 ± 1.1) while the selectivity indexes (CC50/EC50=SI) were: 3g SI (MTT = 127; NR = 130; VC = 133); 3h SI (MTT = 237; NR = 230; VC = 250) and 3i SI (MTT = 155; NR = 165; VC = 169).  Docking simulations revealed that all three ligands exhibited favorable interactions with NS3 and NS5 proteins, both essential for viral replication and virion production. NS5 protein-3h presented the strongest interaction, possibly due to the meta position of its nitro group, which reduces steric hindrance, improves conformational freedom, minimizes interference with hydrogen bonding, and potentially enhances hydrophobic interactions and pi-stacking with protein residues. Our in vitro and in silico findings suggest that these three bis-naphthoquinones, especially 3h, are potential inhibitors of ZIKV replication and, therefore, worthy of future validation experiments.

Palavras Chave

Arbovirus; Molecular docking; bis-naftoquinone