Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro
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Thames, Joy E., Charles D. Waters, Coralie Valle, Marcella Bassetto, Wahiba Aouadi, Baptiste Martin, Barbara Selisko, et al. “Synthesis and Biological Evaluation of Novel Flexible Nucleoside Analogues That Inhibit Flavivirus Replication in Vitro.” Bioorganic & Medicinal Chemistry 28, no. 22 (November 15, 2020): 115713. https://doi.org/10.1016/j.bmc.2020.115713.
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Abstract
Flaviviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, represent a severe health burden. There are currently no FDA-approved treatments, and vaccines against most flaviviruses are still lacking. We have developed several flexible analogues (“fleximers”) of the FDA-approved nucleoside Acyclovir that exhibit activity against various RNA viruses, demonstrating their broad-spectrum potential. The current study reports activity against DENV and Yellow Fever Virus (YFV), particularly for compound 1. Studies to elucidate the mechanism of action suggest the flex-analogue triphosphates, especially 1-TP, inhibit DENV and ZIKV methyltransferases, and a secondary, albeit weak, effect on the DENV RNA-dependent RNA polymerase was observed at high concentrations. The results of these studies are reported herein.