Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

• 成果类型: Article
• 署名作者: Tsukamoto, Yuta; Hiono, Takahiro; Yamada, Shintaro; Matsuno, Keita; Faist, Aileen; Claff, Tobias; Hou, Jianyu; Namasivayam, Vigneshwaran; vom Hemdt, Anja; Sugimoto, Satoko; Ng, Jin Ying; Christensen, Maria H.; Tesfamariam, Yonas M.; Wolter, Steven; Juranek, Stefan; Zillinger, Thomas; Bauer, Stefan; Hirokawa, Takatsugu; Schmidt, Florian I.; Kochs, Georg; Shimojima, Masayuki; Huang, Yi-Shuian; Pichlmair, Andreas; Kuemmerer, Beate M.; Sakoda, Yoshihiro; Schlee, Martin; Brunotte, Linda; Mueller, Christa E.; Igarashi, Manabu; Kato, Hiroki
• 署名单位: University of Bonn; Hokkaido University; Hokkaido University; Hokkaido University; Hokkaido University; University of Munster; University of Bonn; University of Bonn; Japan Institute for Health Security (JIHS); National Institute of Infectious Diseases (NIID); University of Bonn; University of Bonn; University of Bonn; Philipps University Marburg; Aarhus University; University of Tsukuba; University of Tsukuba; National Institute of Advanced Industrial Science & Technology (AIST); University of Bonn; University of Freiburg; University of Freiburg; Academia Sinica - Taiwan; Academia Sinica - Taiwan; Technical University of Munich; German Center for Infection Research; German Center for Infection Research; Hokkaido University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8245
• DOI: 10.1126/science.add0875
• 发表日期: 2023-02-10
• 页码: 586-591
• 关键词: accurate docking; messenger-rna; cap; mechanism; glide

摘要

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.