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
• Antiviral Agents * chemistry   pharmacology   metabolism   MeSH
• Flaviviridae * enzymology   MeSH
• Guanosine Triphosphate * analogs & derivatives   metabolism   chemistry   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Methyltransferases * metabolism   chemistry   genetics   MeSH
• Models, Molecular MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Viral Proteins * metabolism   chemistry   MeSH
• Zika Virus * enzymology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents * MeSH
• Guanosine Triphosphate * MeSH
• Methyltransferases * MeSH
• Viral Proteins * MeSH