Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts.
Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts.
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DOI：
10.1371/journal.pone.0019825
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kuzuhara T
中科院分区：
文献类型：
--
作者：
Iwai Y;Murakami K;Gomi Y;Hashimoto T;Asakawa Y;Okuno Y;Ishikawa T;Hatakeyama D;Echigo N;Kuzuhara T
猪源性H1N1甲型流感病毒于2009年在全世界引起大流行，高致病性H5 N1禽流感病毒近年来也在东南亚引起流行。因此，甲型流感的威胁仍然是一个严重的全球健康问题，并且非常需要靶向这些病毒的新型药物。甲型流感病毒在其RNA聚合酶内具有核酸内切酶，其包含PA、PB 1和PB 2亚基。为了在我们目前的研究中鉴定潜在的新的抗流感化合物，我们使用体外PA核酸内切酶抑制测定和抗甲型流感病毒测定筛选了33种不同类型的植物化学物质。马钱丁是在苔类植物中发现的大环双联苄类化合物，而plagiochin A和perrottetin F是马钱丁相关的植物化学物质。我们从我们的筛选中发现，marchantin A、B、E、plagiochin A和perrottetin F在体外抑制流感PA核酸内切酶活性。这些化合物具有共同的3，4-二羟基苯乙基基团，表明该部分对于抑制PA核酸内切酶的重要性。对接模拟马钱丁E与PA核酸内切酶提出了一个假定的“拟合和螯合模型”的机制PA核酸内切酶抑制。对接氨基酸在甲型流感和B流感之间是很保守的。在培养的细胞系统中，进一步发现马钱丁E抑制H3 N2和H1 N1甲型流感病毒的生长，并且马钱丁A、E和perrotein F显示出对B型流感病毒生长的抑制特性。这些marchantins也降低了病毒感染性滴度，marchantin E在该试验中显示出最强的活性。我们还鉴定了一个在不同抗流感化学品中保守的化学基团，包括马钱汀、绿色茶儿茶素和二羟基苯乙基苯基邻苯二甲酰亚胺。我们目前的研究结果表明，marchantins是候选的抗流感药物，并证明了实用程序的PA核酸内切酶测定抗流感特性的植物化学物质的筛选。
The H1N1 influenza A virus of swine-origin caused pandemics throughout the world in 2009 and the highly pathogenic H5N1 avian influenza virus has also caused epidemics in Southeast Asia in recent years. The threat of influenza A thus remains a serious global health issue and novel drugs that target these viruses are highly desirable. Influenza A possesses an endonuclease within its RNA polymerase which comprises PA, PB1 and PB2 subunits. To identify potential new anti-influenza compounds in our current study, we screened 33 different types of phytochemicals using a PA endonuclease inhibition assay in vitro and an anti-influenza A virus assay. The marchantins are macrocyclic bisbibenzyls found in liverworts, and plagiochin A and perrottetin F are marchantin-related phytochemicals. We found from our screen that marchantin A, B, E, plagiochin A and perrottetin F inhibit influenza PA endonuclease activity in vitro. These compounds have a 3,4-dihydroxyphenethyl group in common, indicating the importance of this moiety for the inhibition of PA endonuclease. Docking simulations of marchantin E with PA endonuclease suggest a putative “fitting and chelating model” as the mechanism underlying PA endonuclease inhibition. The docking amino acids are well conserved between influenza A and B. In a cultured cell system, marchantin E was further found to inhibit the growth of both H3N2 and H1N1 influenza A viruses, and marchantin A, E and perrotein F showed inhibitory properties towards the growth of influenza B. These marchantins also decreased the viral infectivity titer, with marchantin E showing the strongest activity in this assay. We additionally identified a chemical group that is conserved among different anti-influenza chemicals including marchantins, green tea catechins and dihydroxy phenethylphenylphthalimides. Our present results indicate that marchantins are candidate anti-influenza drugs and demonstrate the utility of the PA endonuclease assay in the screening of phytochemicals for anti-influenza characteristics.
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影响因子：
64.8
作者：
Collins, Patrick J.;Haire, Lesley F.;Gamblin, Steven J.
通讯作者：
Gamblin, Steven J.
影响因子：
158.5
作者：
Hayden, FG;Atmar, RL;Mills, RG
通讯作者：
Mills, RG
DOI：
10.1038/nrd2175
发表时间：
2006-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
De Clercq E
通讯作者：
De Clercq E
影响因子：
64.8
作者：
Dias, Alexandre;Bouvier, Denis;Ruigrok, Rob W. H.
通讯作者：
Ruigrok, Rob W. H.
影响因子：
4.8
作者：
Kuzuhara, Takashi;Kise, Daisuke;Tsuge, Hideaki
通讯作者：
Tsuge, Hideaki