Mesoionic heterocyclic compounds as candidate messenger RNA cap analogue inhibitors of the influenza virus RNA polymerase cap-binding activity.

Abstract

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.

• Authors: Ian Mickleburgh, Feng Geng, Laurence Tiley
• Journal: Antiviral chemistry & chemotherapy (Antivir Chem Chemother) Vol. 19 Issue 5 Pg. 213-8 ( 2009) ISSN: 2040-2066 [Electronic] England
• PMID: 19483269 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds
• PB2 protein, influenza virus
• RNA Cap Analogs
• Viral Proteins
• Guanine
• 7-methylguanine
• DNA-Directed RNA Polymerases

Topics

• DNA-Directed RNA Polymerases (antagonists & inhibitors)
• Guanine (analogs & derivatives, chemistry)
• Heterocyclic Compounds (pharmacology, therapeutic use)
• Orthomyxoviridae (enzymology)
• Protein Binding
• RNA Cap Analogs (pharmacology, therapeutic use)
• Structure-Activity Relationship
• Viral Proteins (antagonists & inhibitors)