Download MendeleyAT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5.
Feracci, M., Eydoux, C., Fattorini, V., Lo Bello, L., Gauffre, P., Selisko, B., Sutto-Ortiz, P., Shannon, A., Xia, H., Shi, P.Y., Noel, M., Debart, F., Vasseur, J.J., Good, S., Lin, K., Moussa, A., Sommadossi, J.P., Chazot, A., Alvarez, K., Guillemot, J.C., Decroly, E., Ferron, F., Canard, B.(2023) Antiviral Res 212: 105574-105574
- PubMed: 36905944
- DOI: https://doi.org/10.1016/j.antiviral.2023.105574
- Primary Citation of Related Structures:
8BCR - PubMed Abstract:
AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. Crystal structure and RNA methyltransferase (MTase) activities of the DENV 2 MTase domain in complex with AT-9010 at 1.97?? resolution shows the latter bound to the GTP/RNA-cap binding site, accounting for the observed inhibition of 2'-O but not N7-methylation activity. AT-9010 is discriminated ¡«10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibition through viral RNA synthesis termination. In Huh-7?cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC 50 ?¡Ö?0.50?¦̀M), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses.
Organizational Affiliation:
AFMB, CNRS, Aix-Marseille University, UMR 7257, Case 925, 163 Avenue de Luminy, 13288, Marseille Cedex 09, France.
