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Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication.

Science (New York, N.Y.)

Authors: 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

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 , called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its -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.

PMID: 36758070

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