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

Mikael Feracci, Cécilia Eydoux, Véronique Fattorini, Lea Lo Bello, Pierre Gauffre, Barbara Selisko, Priscila Sutto-Ortiz, Ashleigh Shannon, Hongjie Xia, Pei Yong Shi, Mathieu Noel, Françoise Debart, Jean Jacques Vasseur, Steve Good, Kai Lin, Adel Moussa, Jean Pierre Sommadossi, Aurélie Chazot, Karine Alvarez, Jean Claude GuillemotEtienne Decroly, François Ferron, Bruno Canard

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 Å 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 (EC50 ≈ 0.50 μM), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses.

Original languageEnglish (US)
Article number105574
JournalAntiviral research
Volume212
DOIs
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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