1区 · 综合性期刊
Article
作者: Schlee, Martin ; Huang, Yi-Shuian ; Hiono, Takahiro ; Kato, Hiroki ; Vom Hemdt, Anja ; Brunotte, Linda ; Bauer, Stefan ; Sugimoto, Satoko ; Juranek, Stefan ; Zillinger, Thomas ; Faist, Aileen ; Matsuno, Keita ; Hirokawa, Takatsugu ; Hou, Jianyu ; Tesfamariam, Yonas M ; Kochs, Georg ; Kümmerer, Beate M ; Yamada, Shintaro ; Claff, Tobias ; Christensen, Maria H ; Ng, Jin Ying ; Igarashi, Manabu ; Shimojima, Masayuki ; Pichlmair, Andreas ; Wolter, Steven ; Namasivayam, Vigneshwaran ; Tsukamoto, Yuta ; Müller, Christa E ; Schmidt, Florian I ; Sakoda, Yoshihiro
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.
