Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
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DOI：
10.1126/science.add0875
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发表时间：
2023-02-10
期刊：
影响因子：
56.9
通讯作者：
Kato, Hiroki
中科院分区：
文献类型：
--
作者：
Tsukamoto, Yuta;Hiono, Takahiro;Kato, Hiroki
正粘病毒和布尼亚病毒窃取宿主RNA的5‘帽部分，以启动自己的转录，这一过程被称为“帽子抢夺”。我们报道，宿主2‘-O-核糖甲基转移酶1(MTr1)对帽部分的RNA修饰是启动甲型和乙型流感病毒复制所必需的，但对其他抢帽病毒来说不是。我们通过电子筛选和功能分析鉴定了一种来自链霉菌的天然产物的衍生物，称为三氟甲基-结瘤素，它通过与S-腺苷-L-蛋氨酸结合口袋的相互作用来抑制MTr1，从而限制流感病毒的复制。从机制上讲，TFMT在人肺外植体和小鼠体内损害宿主帽RNA与病毒聚合酶碱性蛋白2亚单位的联系。TFMT与批准的抗流感药物具有协同作用。
Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-L-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.