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

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; Kümmerer, Beate M; Sakoda, Yoshihiro; Schlee, Martin; Brunotte, Linda; Müller, Christa E; Igarashi, Manabu; Kato, Hiroki     «

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; Kümmerer, Beate M; Sakoda, Yoshihiro; Schlee, Martin; Brunotte, Linda; Müller, Christa E...     »

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.      «

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-tuber...     »