AT-9010 (2'-methyl-2'-fluoro guanosine triphosphate) is a GTP analog whose prodrug, AT-752 is under consideration in human medicine as a potential antiviral drug against certain flaviviruses. It was previously believed to inhibit viral replication by acting primarily as a chain terminator. However, it was discovered recently that it also binds the GTP binding site of the methyltransferase (MTase) domain of the orthoflavivirus polymerase, thus interfering with RNA capping. Here, we investigated the binding of AT-9010 to Ntaya and Zika virus MTases. Structural analysis using X-ray crystallography revealed similar interactions between the base and sugar moieties of AT-9010 and key residues in both MTases, although differences in hydrogen bonding were observed. Our analysis also suggested that the triphosphate part of AT-9010 is flexible. Despite minor variations, the overall binding mode of AT-9010 was found to be the same for all of the flaviviral MTases examined, suggesting a structural basis for the efficacy of AT-9010 against multiple orthoflavivirus MTases.

• MeSH
• antivirové látky * chemie   farmakologie   metabolismus   MeSH
• Flaviviridae * enzymologie   MeSH
• guanosintrifosfát * analogy a deriváty   metabolismus   chemie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• methyltransferasy * metabolismus   chemie   genetika   MeSH
• molekulární modely MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• virové proteiny * metabolismus   chemie   MeSH
• virus zika * enzymologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky * MeSH
• guanosintrifosfát * MeSH
• methyltransferasy * MeSH
• virové proteiny * MeSH

Zika virus is a global health threat due to significantly elevated risk of fetus malformations in infected pregnant women. Currently, neither an effective therapy nor a prophylactic vaccination is available for clinical use, desperately necessitating novel therapeutics and approaches to obtain them. Here, we present a structural model of the Zika virus RNA-dependent RNA polymerase (ZIKV RdRp) in complex with template and nascent RNAs, Mg2+ ions and accessing nucleoside triphosphate. The model allowed for docking studies aimed at effective pre-screening of potential inhibitors of ZIKV RdRp. Applicability of the structural model for docking studies was illustrated with the NITD008 artificial nucleotide that is known to effectively inhibit the function of the ZIKV RdRp. The ZIKV RdRp - RNA structural model is provided for all possible variations of the nascent RNA bases pairs to enhance its general utility in docking and modelling experiments. The developed model makes the rational design of novel nucleosides and nucleotide analogues feasible and thus provides a solid platform for the development of advanced antiviral therapy.

• MeSH
• adenosin analogy a deriváty   chemie   farmakologie   MeSH
• hořčík chemie   MeSH
• infekce virem zika genetika   virologie   MeSH
• konformace proteinů účinky léků   MeSH
• lidé MeSH
• molekulární modely MeSH
• nukleosidy chemie   MeSH
• nukleotidy chemie   MeSH
• polyfosfáty chemie   MeSH
• replikace viru genetika   MeSH
• RNA-dependentní RNA-polymerasa chemie   genetika   MeSH
• RNA chemie   genetika   MeSH
• simulace molekulového dockingu MeSH
• virové nestrukturální proteiny chemie   genetika   MeSH
• virus zika chemie   genetika   patogenita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• hořčík MeSH
• NITD008 MeSH Prohlížeč
• nukleosidy MeSH
• nukleotidy MeSH
• polyfosfáty MeSH
• RNA-dependentní RNA-polymerasa MeSH
• RNA MeSH
• triphosphoric acid MeSH Prohlížeč
• virové nestrukturální proteiny MeSH