Mesoionic heterocyclic compounds as candidate messenger RNA cap analogue inhibitors of the influenza virus RNA polymerase cap-binding activity.
BACKGROUND
An unusual feature of influenza viral -messenger RNA (mRNA) synthesis is its dependence upon host cell mRNAs as a source of capped RNA primers. A crucial activity of the influenza polymerase is to steal these primers by binding and cleaving the caps from host mRNAs. The recent structural analysis of the cap-binding fragment of the influenza virus PB2 protein has highlighted the importance of the mesoionic properties of the N7-methylguanine (N(7m)G) component of the mRNA cap in this interaction.


METHODS
A series of mesoionic heterocycles with 5,6-fused ring systems analogous to the N(7m)G component of mRNA cap structures were synthesized and examined for the ability to inhibit the cap-binding activity of the influenza virus RNA polymerase complex using a bead-based in vitro cap-binding assay.


RESULTS
None of the compounds tested were able to significantly inhibit binding and subsequent endonucleolytic cleavage of a synthetic radiolabelled capped mRNA substrate by recombinant influenza virus polymerase in vitro.


CONCLUSIONS
Compounds analogous to the mesoionic N(7m)G component of mRNA cap structures comprise a large class of potential inhibitors of the influenza virus polymerase. Although this preliminary assessment of a small group of related analogues was unsuccessful, further screening of this class of compounds is warranted.
Mickleburgh
Ian
I
Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Geng
Feng
F
Tiley
Laurence
L
D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D009975:Orthomyxoviridae / Q000201:enzymology*; D011485:Protein Binding; D012314:RNA Cap Analogs / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors
D006571:Heterocyclic Compounds; C502893:PB2 protein, influenza virus; D012314:RNA Cap Analogs; D014764:Viral Proteins; D006147:Guanine; C008450:7-methylguanine; D012321:DNA-Directed RNA Polymerases