Cellular Mechanism of Flavonoid Derivatives Inhibiting Dengue Virus Infectivity

Abstract

Dengue virus infection is a global public health threat where specific treatment has not been established. Chrysin and flavanone derivatives were previously reported as potential anti-flaviviral inhibitors. We explored ten flavones, flavanones, chalcone, and anthraquinone derivatives that extracted and modified from natural products.Two chrysin derivatives showed inhibitory effects against DENV1-4 and ZIKV SV0010/15 infectivities with the EC50 values of 2.30±1.04, 1.47±0.86, 2.32±1.46, 1.78±0.72 and 1.65±0.86 µM of FV13 and 2.30±0.92, 2.19±0.31, 1.02±0.31, 1.29±0.60 and 1.39±0.11 µM of FV14 respectively. The CC50s to LLC/MK2 of FV13 and FV14 were 44.58±2.99 and 44.51±2.58 µM, respectively. Time of addition assay revealed that the primary target was at early after infection. We observed that the compound did not interfere with the viral attachment, but rather showed its highest efficacy at post-attachment with viral titer inhibition of 64.97±1.18% and viral RNA inhibition of 59.96±4.56%. To confirm the replication inhibition, we tested with BHK-21/DENV2 replicon cells. We found that viral replication inhibition of 10 µM FV13 was 75.38 ± 7.88 %. This report demonstrated for the first time as a potential candidates to inhibit the dengue and Zika infectivities with high efficacy at micromolar level that could be developed as a broad-spectrum anti-flaviviral drug. This study also provided insights in cellular toxicity, stability, and suggested possible drug targets for further optimization.