PA subunit of RNA polymerase as a promising target for anti-influenza virus agents.
RNA polymerase of influenza virus is a specific enzyme necessary for the viral replication. A siRNA against the RNA polymerase and the RNA polymerase inhibitor L-742,001 reduced accumulation of viral RNAs in the infected cells. L-742,001 strongly inhibited virus re-growth after removal of the agent from the culture, whereas the neuraminidase inhibitor zanamivir did not. L-742,001-resistant mutants showed a Thr-20 to Ala substitution in the PA subunit of RNA polymerase. The drug-resistant virus showed a slight reduction in the susceptibility to L-742,001 in both the plaque assay (threefold reduction) and enzyme assay (two- to three-fold reduction). The resistance levels were lower than those of zanamivir-resistant mutants in the plaque assay. Against zanamivir-resistant mutants, L-742,001 retained the same antiviral activity as against the wild-type strain. These results indicate that L-742,001 is most likely to act at the PA subunit, and possesses a unique profile. It is suggested that PA subunit of RNA polymerase is a promising target for anti-influenza virus agents.
Nakazawa
Misako
M
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., Tochigi 329-0114, Japan. misako.nakazawa@mb.kyorin-pharm.co.jp
Kadowaki
Shin-etsu
SE
Watanabe
Izumi
I
Kadowaki
Youko
Y
Takei
Masaya
M
Fukuda
Hideyuki
H
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D053243:Zanamivir / Q000494:pharmacology
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; C585288:L-742,001; C061290:PA protein, influenza viruses; D010880:Piperidines; D034741:RNA, Small Interfering; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; D053243:Zanamivir