Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.
Stimulation of alpha2-adrenergic receptors impairs influenza virus infection.
复制标题
DOI：
10.1038/s41598-018-22927-0
复制
发表时间：
2018-03-15
影响因子：
4.6
通讯作者：
Kawaoka Y
中科院分区：
文献类型：
--
作者：
Matsui K;Ozawa M;Kiso M;Yamashita M;Maekawa T;Kubota M;Sugano S;Kawaoka Y
甲型流感病毒引起季节性流行病和偶尔的大流行。对神经氨酸酶（NA）抑制剂和M2离子通道抑制剂耐药的病毒的出现，强调了对具有新作用机制的替代抗流感药物的需求。在这里，我们报告宿主因子作为抗流感药物的潜在靶点的发现。通过基于细胞的病毒复制筛选化学文库和一些额外的试验，我们确定可乐定是一种新的体外抗流感剂。我们发现可乐定是α2-肾上腺素能受体（α2-AR）的激动剂，对多种流感病毒株的复制有抑制作用。α2-AR是一种降低细胞内环AMP （cAMP）水平的gi型G蛋白偶联受体。深入分析表明，α2-AR刺激可导致流感病毒复制受损，α2-AR激动剂可能通过camp介导的途径抑制病毒组装步骤。虽然给药可乐定不能降低肺病毒滴度或防止体重减轻，但在小鼠致死性感染模型中，它确实抑制肺水肿并提高生存率。因此，可乐定可以防止流感病毒感染引起的肺损伤。我们的研究结果确定α2- ar介导的信号通路是开发抗流感药物的关键途径。
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 (α2-AR), has an inhibitory effect on the replication of various influenza virus strains. α2-AR is a Gi-type G protein-coupled receptor that reduces intracellular cyclic AMP (cAMP) levels. In-depth analysis showed that stimulation of α2-ARs leads to impairment of influenza virus replication and that α2-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 α2-AR-mediated signaling as a key pathway to exploit in the development of anti-influenza agents.
登录
查看更多内容
影响因子：
2.7
作者：
Fonseca, Wendy;Ozawa, Makoto;Hatta, Masato;Orozco, Esther;Martinez, Maximo B.;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
Toll样受体（TLR）3对病毒诱导的急性肺炎的有害贡献。
影响因子：
6.7
作者：
Le Goffic, Ronan;Balloy, Viviane;Lagranderie, Micheline;Alexopoulou, Lena;Escriou, Nicolas;Flavell, Richard;Chignard, Michel;Si-Tahar, Mustapha
通讯作者：
Si-Tahar, Mustapha
DOI：
10.1017/s1461145709991088
发表时间：
2010-10-01
影响因子：
4.8
作者：
Dwyer, Jason M.;Platt, Brian J.;Beyer, Chad E.
通讯作者：
Beyer, Chad E.
影响因子：
9.4
作者：
Hatakeyama, S;Sakai-Tagawa, Y;Kawaoka, Y
通讯作者：
Kawaoka, Y
影响因子：
5.8
作者：
Ohuchi, Masanobu;Asaoka, Naoko;Ohuchi, Reiko
通讯作者：
Ohuchi, Reiko