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Article Dans Une Revue Antiviral Research Année : 2023

AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5

Hongjie Xia
Pei-Yong Shi
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Steve Good
Kai Lin
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Adel Moussa
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Jean-Pierre Sommadossi
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Résumé

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 angstrom 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 inhibi-tion through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC50 approximate to 0.50 mu M), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses.
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Dates et versions

hal-04159074 , version 1 (11-07-2023)

Identifiants

Citer

Mikael Feracci, Cécilia Eydoux, Véronique Fattorini, Lea Lo Bello, Pierre Gauffre, et al.. AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5. Antiviral Research, 2023, 212, pp.105574. ⟨10.1016/j.antiviral.2023.105574⟩. ⟨hal-04159074⟩
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