Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-22927-0
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan
- Japan Initiative for Global Research Network on Infectious Diseases from MEXT, Japan
- Japan Agency for Medical Research and Development (AMED)
- Japan Science and Technology Agency
- AMED [JP17am0001007]
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Influenza A viruses cause seasonal epidemics and occasional pandemics. The emergence of viruses resistant to neuraminidase (NA) inhibitors and M2 ion channel inhibitors underlines the need for alternate anti-influenza drugs with novel mechanisms of action. Here, we report the discovery of a host factor as a potential target of anti-influenza drugs. By using cell-based virus replication screening of a chemical library and several additional assays, we identified clonidine as a new anti-influenza agent in vitro. We found that clonidine, which is an agonist of the alpha2-adrenergic receptor (alpha 2-AR), has an inhibitory effect on the replication of various influenza virus strains. alpha 2-AR is a Gi-type G proteincoupled receptor that reduces intracellular cyclic AMP (cAMP) levels. In-depth analysis showed that stimulation of alpha 2-ARs leads to impairment of influenza virus replication and that alpha 2-AR agonists inhibit the virus assembly step, likely via a cAMP-mediated pathway. Although clonidine administration did not reduce lung virus titers or prevent body weight loss, it did suppress lung edema and improve survival in a murine lethal infection model. Clonidine may thus protect against lung damage caused by influenza virus infection. Our results identify alpha 2-AR-mediated signaling as a key pathway to exploit in the development of anti-influenza agents.
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