Antiviral activity of diarylheptanoid stereoisomers against respiratory syncytial virus in vitro and in vivo.
We previously showed that (5S)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenylhept-3-one (AO-0011) and (5S)-5-methoxy-1,7-diphenylhept-3-one (AO-0016) isolated from Alpinia officinarum exhibited stronger anti-influenza virus activity and anti-respiratory syncytial virus (RSV) activity, respectively, than the other isolated diarylheptanoids. In this study, we synthesized an enantiomer (AO-0503) and racemate (AO-0504) of AO-0011 and an enantiomer (AO-0514) of AO-0016. The anti-RSV activities of the three stereoisomers (AO-0503, AO-0504, and AO-0514) and AO-0011 were examined in vitro and in vivo to evaluate the stereoisomeric effect on anti-RSV activity. In a plaque reduction assay using human epidermoid carcinoma cells, all four diarylheptanoids significantly exhibited anti-RSV activity, and AO-0514 and AO-0016 exhibited stronger anti-RSV activity than AO-0503, AO-0504, and AO-0011. In a murine RSV infection model, all four diarylheptanoids with anti-RSV activity in vitro were also significantly effective in reducing virus titers in the lungs of RSV-infected mice. In the histopathological analysis of RSV-infected lungs, the oral administration of even AO-0514, which showed the lowest reduction of virus titers in the lungs, was significantly effective in reducing the infiltration of lymphocytes and in reducing the interferon-γ level, which is a marker of severity of pneumonia due to RSV infection, in bronchoalveolar lavage fluids prepared from RSV-infected mice. Although the stereoisomeric effects of diarylheptanoids on anti-RSV activity varied moderately, all four diarylheptanoids examined were suggested to ameliorate pneumonia and have a potential anti-RSV activity in vivo. They are possibly mother compounds for the development of an anti-RSV drug in the future.
Department of Clinical Veterinary Medicine, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki, 882-8508, Japan.
Katsuhiko
K
Konno
Motofumi
M
Miura
Masaharu
M
Toriyama
Shigeyasu
S
Motohashi
Rie
R
Sawamura
Wataru
W
Watanabe
Hiroki
H
Yoshida
Masahiko
M
Kato
Ryuichi
R
Yamamoto
Ken
K
Yasukawa
Masahiko
M
Kurokawa
D032429:Alpinia / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D036381:Diarylheptanoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013237:Stereoisomerism
D000998:Antiviral Agents; D036381:Diarylheptanoids; D007371:Interferon-gamma