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