Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro

Joy Thames (1) , Charles Waters (1) , Coralie Valle (2) , Marcella Bassetto (3) , Wahiba Aouadi (2) , Baptiste Martin (2) , Barbara Selisko (2) , Arissa Falat (1) , Bruno Coutard (4) , Andrea Brancale (5) , Bruno Canard (2) , Etienne Decroly (2) , Katherine Seley-Radtke (6)

1 University of Maryland School of Medicine
2 AFMB - Architecture et fonction des macromolécules biologiques
3 Swansea University
4 UVE - Unité des Virus Emergents
5 Cardiff University
6 UMSOD - University of Maryland School of Dentistry [Baltimore]

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.

Mots clés: :Flavivirus; Dengue; Zika; Yellow Fever; Methyltransferase; Nucleoside; Fleximers; Acyclovir

Domaines: Sciences du Vivant [q-bio]

Joy Thames, Charles Waters, Coralie Valle, Marcella Bassetto, Wahiba Aouadi, et al.. Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro. Bioorganic and Medicinal Chemistry Letters, 2020, 28 (22), pp.115713. ⟨10.1016/j.bmc.2020.115713⟩. ⟨hal-03030860⟩