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

Monkeypox, or mpox, is a disease that has recently resurfaced and spread across the globe. Despite the availability of an FDA-approved vaccine (JYNNEOS) and an effective drug (tecovirimat), concerns remain over the possible recurrence of a viral pandemic. Like any other virus, mpox virus must overcome the immune system to replicate. Viruses have evolved various strategies to overcome both innate and adaptive immunity. Poxviruses possess an unusual nuclease, poxin, which cleaves 2'-3'-cGAMP, a cyclic dinucleotide, which is an important second messenger in the cGAS-STING signaling pathway. Here, we present the crystal structure of mpox poxin. The structure reveals a conserved, predominantly β-sheet fold and highlights the high conservation of the cGAMP binding site and of the catalytic residues His17, Tyr138, and Lys142. This research suggests that poxin inhibitors could be effective against multiple poxviruses.

• MeSH
• lidé MeSH
• opičí neštovice * MeSH
• Poxviridae * MeSH
• racionální návrh léčiv MeSH
• signální transdukce MeSH
• virus opičích neštovic MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH