Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743
Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743
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Flupyranochromene 是一种新型流感病毒帽依赖性核酸内切酶抑制剂，来自青霉属。
DOI：
10.1038/s41429-018-0134-z
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Nomoto Akio
中科院分区：
文献类型：
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作者：
Yamasaki Manabu;Igarashi Masayuki;Sawa Ryuichi;Nosaka Chisato;Umekita Maya;Hatano Masaki;Kimura Tomoyuki;Iijima Kiyoko;Takizawa Naoki;Kato Taira;Mizumoto Kiyohisa;Nomoto Akio
流感病毒RNA聚合酶具有帽依赖性内切酶活性，可产生帽状RNA片段，用于启动病毒mRNA合成。这种酶活性对病毒繁殖至关重要，但它不存在于任何宿主细胞酶中，使其成为抗流感药物开发的一个有吸引力的靶标。在这里，我们从真菌青霉菌的发酵液中分离出一种新的帽依赖性内切酶抑制剂，命名为氟吡喃铬烯。f28743。结构分析表明，该化合物含有一个假定的药效团，可以螯合聚合酶PA亚基内切酶活性位点上的二价金属离子。与此一致的是，体外核酸内切酶实验表明，氟吡喃铬烯通过阻断病毒RNA聚合酶复合物PA亚基的内切作用来发挥其抑制作用。
Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungusPenicilliumsp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.