In vitro and in vivo anti-influenza virus activity of diarylheptanoids isolated from Alpinia officinarum.
BACKGROUND
Diarylheptanoids (AO-0002 [7-(4''-hydroxy-3''-methoxyphenyl)-1-phenyl-4E-hepten-3-one] and AO-0011 [(5S)-5-hydroxy-7-(4''-hydroxyphenyl)-1-phenyl-3-heptanone]) isolated from Alpinia officinarum have been reported to exhibit anti-influenza virus activity in vitro. Hence, efficacies against influenza virus infection and the mode of antiviral action were evaluated in vivo and in vitro, respectively.


METHODS
In a murine influenza virus infection model, diarylheptanoids were orally administered three times daily to mice infected with influenza A/PR/8/34 virus for 6 days after infection. AO-0002 was examined for its antiviral activity against the wild types of influenza viruses A/PR/8/34 (H1N1), oseltamivir-resistant A/PR/8/34 (H1N1), A/Bangkok/93/03 (H1N1), A/Ishikawa/7/82 (H3N2), A/Fukushima/13/43 (H3N2), B/Singapore/222/79 and B/Fukushima/15/93 in plaque reduction or yield reduction assays. The mode of anti-influenza virus action was assessed by a virus adsorption assay, immunofluorescence assay of viral antigens, and inhibition of viral messenger RNA synthesis using real-time reverse transcriptase PCR.


RESULTS
AO-0002 at 100 mg/kg was significantly effective in reducing the body weight loss and prolonging survival times of infected mice without toxicity, but AO-0011 was not. AO-0002 at 30 and 100 mg/kg significantly reduced virus titres in bronchoalveolar lavage fluids of the lungs on days 3 and 6 after infection. AO-0002 exhibited anti-influenza virus activity against all viruses used, including the oseltamivir-resistant strain in vitro. The compound had no effect on virus adsorption or invasion into cells, but dose-dependently suppressed the expression of viral messenger RNA and antigens.


CONCLUSIONS
AO-0002 was suggested to have a different anti-influenza virus action to that of oseltamivir and was verified to show anti-influenza activity in vitro and in vivo.
Department of Biochemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Japan.
Rie
R
Sawamura
Tomomi
T
Shimizu
Yi
Y
Sun
Ken
K
Yasukawa
Motofumi
M
Miura
Masaharu
M
Toriyama
Shigeyasu
S
Motohashi
Wataru
W
Watanabe
Katsuhiko
K
Konno
Masahiko
M
Kurokawa
D032429:Alpinia / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D036381:Diarylheptanoids / Q000302:isolation & purification / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis; D053585:Virus Attachment / Q000187:drug effects
D000998:Antiviral Agents; D036381:Diarylheptanoids; D012333:RNA, Messenger; D012367:RNA, Viral