Q1 · CROSS-FIELD
Article
Author: Yamada, Shintaro ; Juranek, Stefan ; Wolter, Steven ; Matsuno, Keita ; Kümmerer, Beate M ; Christensen, Maria H ; Vom Hemdt, Anja ; Claff, Tobias ; Sugimoto, Satoko ; Zillinger, Thomas ; Pichlmair, Andreas ; Kochs, Georg ; Schmidt, Florian I ; Hiono, Takahiro ; Bauer, Stefan ; Shimojima, Masayuki ; Huang, Yi-Shuian ; Brunotte, Linda ; Sakoda, Yoshihiro ; Tsukamoto, Yuta ; Schlee, Martin ; Kato, Hiroki ; Hou, Jianyu ; Tesfamariam, Yonas M ; Müller, Christa E ; Namasivayam, Vigneshwaran ; Faist, Aileen ; Ng, Jin Ying ; Igarashi, Manabu ; Hirokawa, Takatsugu
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.