德国波恩大学Hiroki Kato等研究人员合作发现，抑制细胞RNA甲基转移酶阻断流感病毒的加帽和复制
研究人员报道了宿主2′-O-核糖甲基转移酶1（MTr1）对帽部的RNA修饰对甲型和乙型流感病毒复制的启动是必不可少的，但对其他帽掠夺病毒则不是。研究人员在计算化合物筛选和功能分析中发现了链霉菌天然产物的衍生物，称为三氟甲基-结核霉素（TFMT），它通过在MTr1的S-腺苷-l-蛋氨酸结合口袋中相互作用来抑制MTr1，从而限制流感病毒的复制。在机制上，TFMT在人肺外植体和小鼠体内破坏宿主帽RNA与病毒聚合酶碱性蛋白2亚基的关联。TFMT与已批准的抗流感药物协同作用。
据介绍，正黏液病毒和布尼亚病毒科窃取宿主RNA的5'帽部分，在称为“帽掠夺”的过程中启动自己的转录。
附：英文原文
Title: Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
Author: Yuta Tsukamoto, Takahiro Hiono, Shintaro Yamada, Keita Matsuno, Aileen Faist, Tobias Claff, Jianyu Hou, Vigneshwaran Namasivayam, Anja vom Hemdt, Satoko Sugimoto, Jin Ying Ng, Maria H. Christensen, Yonas M. Tesfamariam, Steven Wolter, Stefan Juranek, Thomas Zillinger, Stefan Bauer, Takatsugu Hirokawa, Florian I. Schmidt, Georg Kochs, Masayuki Shimojima, Yi-Shuian Huang, Andreas Pichlmair, Beate M. Kümmerer, Yoshihiro Sakoda, Martin Schlee, Linda Brunotte, Christa E. Müller, Manabu Igarashi, Hiroki Kato
Issue&Volume: 2023-02-10
Abstract: 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.
DOI: add0875
Source: https://www.science.org/doi/10.1126/science.add0875