Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression
Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression
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Leucomycin A3 是一种 16 元大环内酯类抗生素，可抑制甲型流感病毒感染和疾病进展
DOI：
10.1038/ja.2013.132
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发表时间：
2014
期刊：
影响因子：
3.3
通讯作者：
Kazuo Suzuki
中科院分区：
文献类型：
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作者：
Ryuichi Sugamata;Akihiro Sugawara;Tomokazu Nagao;Koya Suzuki;Tomoyasu Hirose;Ki-ichi Yamamoto;Masamichi Oshima;Kazuo Kobayashi;Toshiaki Sunazuka;Kiyoko S Akagawa;Satoshi Omura;Toshinori Nakayama;Kazuo Suzuki
流感病毒感染引起的严重呼吸道疾病死亡率很高。中性粒细胞髓过氧化物酶 (MPO) 与严重流感引起的肺炎的发病机制有关，因为细胞外释放的 MPO 介导次氯酸（一种有效的组织损伤因子）的产生。为了寻找候选抗流感化合物，我们通过分析白霉素 A 3 (LM-A 3)、螺旋霉素 (SPM)、红霉素衍生物（EM900，其中抗菌活性已被消除）和克拉霉素 (CAM) 抑制小鼠和人类中性粒细胞中 MPO 释放的能力来筛选它们。当将每种候选药物注射到感染致死剂量的 A/H1N1 流感病毒 (PR-8) 的小鼠体内时，LM-A 3 产生了最高的存活率 (80.9%)。我们发现 LM-A 3 对肺部病理学和病毒增殖产生有益影响，涉及肺部 MPO 释放、促炎细胞因子和干扰素 α 产生的调节活性。 SPM 和 EM900 还对受感染小鼠产生积极的生存影响，而 CAM 则不然。我们进一步发现这些化合物在体外抑制人肺炎上皮A549细胞中的病毒增殖。 LM-A 3 在人类宿主细胞中表现出对甲型流感病毒感染的有效作用，并具有高抗病毒活性，表明 LM-A 3 可能是开发人类流感药物的潜在先导化合物。 EM900 诱导的积极生存效应表明，抗菌活性和抗流感病毒活性之间的药理学结构可以在大环内酯衍生物中分离。这些观察结果为潜在开发具有强抗病毒但无抗菌活性的新型大环内酯衍生物提供了有价值的证据。
Severe respiratory disease arising from influenza virus infection has a high fatality rate. Neutrophil myeloperoxidase (MPO) has been implicated in the pathogenesis of severe influenza-induced pneumonia because extracellularly released MPO mediates the production of hypochlorous acid, a potent tissue injury factor. To search for candidate anti-influenza compounds, we screened leucomycin A 3 (LM-A 3), spiramycin (SPM), an erythromycin derivative (EM900, in which anti-bacterial activity has been eliminated), and clarithromycin (CAM), by analyzing their ability to inhibit MPO release in neutrophils from mice and humans. When each candidate was injected into mice infected with a lethal dose of A/H1N1 influenza virus (PR-8), LM-A 3 produced the highest survival rate (80.9%). We found that LM-A 3 induced beneficial effects on lung pathology and viral proliferation involved in the regulatory activity of MPO release, pro-inflammatory cytokines and interferon-α production in the lung. SPM and EM900 also induced positive survival effects in the infected mice, whereas CAM did not. We further found that these compounds inhibit virus proliferation in human pneumonia epithelial A549 cells in vitro. LM-A 3 showed effective action against influenza A virus infection with high anti-viral activity in human host cells, indicating the possibility that LM-A 3 is a prospective lead compound for the development of a drug for human influenza. The positive survival effect induced by EM900 suggests that pharmacological architectures between anti-bacterial and anti-influenza virus activities can be dissociated in macrolide derivatives. These observations provide valuable evidence for the potential development of novel macrolide derivatives that have strong anti-viral but no anti-bacterial activity.