| Structural highlights
Function
A9LIE0_9FLAV Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS013754_004_099774]
Publication Abstract from PubMed
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 A 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 approximately 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) approximately 0.50 muM), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses.
AT-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 PY, Noel M, Debart F, Vasseur JJ, Good S, Lin K, Moussa A, Sommadossi JP, Chazot A, Alvarez K, Guillemot JC, Decroly E, Ferron F, Canard B Antiviral Res. 2023 Mar 9;212:105574. doi: 10.1016/j.antiviral.2023.105574. PMID:36905944[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Feracci M, Eydoux C, Fattorini V, Lo Bello L, Gauffre P, Selisko B, Sutto-Ortiz P, Shannon A, Xia H, Shi PY, Noel M, Debart F, Vasseur JJ, Good S, Lin K, Moussa A, Sommadossi JP, Chazot A, Alvarez K, Guillemot JC, Decroly E, Ferron F, Canard B. AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5. Antiviral Res. 2023 Apr;212:105574. PMID:36905944 doi:10.1016/j.antiviral.2023.105574
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