tetano
Editor, Senior Moderator
Science
. 2023 Feb 10;379(6632):586-591.
doi: 10.1126/science.add0875. Epub 2023 Feb 9.
Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
Yuta Tsukamoto[SUP] 1 [/SUP], Takahiro Hiono[SUP] 2 3 [/SUP], Shintaro Yamada[SUP] 1 [/SUP], Keita Matsuno[SUP] 2 4 5 [/SUP], Aileen Faist[SUP] 6 7 [/SUP], Tobias Claff[SUP] 8 [/SUP], Jianyu Hou[SUP] 8 [/SUP], Vigneshwaran Namasivayam[SUP] 8 [/SUP], Anja Vom Hemdt[SUP] 9 [/SUP], Satoko Sugimoto[SUP] 10 [/SUP], Jin Ying Ng[SUP] 1 [/SUP], Maria H Christensen[SUP] 11 [/SUP], Yonas M Tesfamariam[SUP] 11 [/SUP], Steven Wolter[SUP] 12 [/SUP], Stefan Juranek[SUP] 13 [/SUP], Thomas Zillinger[SUP] 12 14 15 [/SUP], Stefan Bauer[SUP] 14 [/SUP], Takatsugu Hirokawa[SUP] 16 17 18 [/SUP], Florian I Schmidt[SUP] 11 19 [/SUP], Georg Kochs[SUP] 20 21 [/SUP], Masayuki Shimojima[SUP] 10 [/SUP], Yi-Shuian Huang[SUP] 22 23 [/SUP], Andreas Pichlmair[SUP] 24 25 [/SUP], Beate M Kümmerer[SUP] 9 26 [/SUP], Yoshihiro Sakoda[SUP] 2 3 [/SUP], Martin Schlee[SUP] 12 [/SUP], Linda Brunotte[SUP] 6 27 [/SUP], Christa E Müller[SUP] 8 [/SUP], Manabu Igarashi[SUP] 2 28 [/SUP], Hiroki Kato[SUP] 1 [/SUP]
Affiliations
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.
. 2023 Feb 10;379(6632):586-591.
doi: 10.1126/science.add0875. Epub 2023 Feb 9.
Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication
Yuta Tsukamoto[SUP] 1 [/SUP], Takahiro Hiono[SUP] 2 3 [/SUP], Shintaro Yamada[SUP] 1 [/SUP], Keita Matsuno[SUP] 2 4 5 [/SUP], Aileen Faist[SUP] 6 7 [/SUP], Tobias Claff[SUP] 8 [/SUP], Jianyu Hou[SUP] 8 [/SUP], Vigneshwaran Namasivayam[SUP] 8 [/SUP], Anja Vom Hemdt[SUP] 9 [/SUP], Satoko Sugimoto[SUP] 10 [/SUP], Jin Ying Ng[SUP] 1 [/SUP], Maria H Christensen[SUP] 11 [/SUP], Yonas M Tesfamariam[SUP] 11 [/SUP], Steven Wolter[SUP] 12 [/SUP], Stefan Juranek[SUP] 13 [/SUP], Thomas Zillinger[SUP] 12 14 15 [/SUP], Stefan Bauer[SUP] 14 [/SUP], Takatsugu Hirokawa[SUP] 16 17 18 [/SUP], Florian I Schmidt[SUP] 11 19 [/SUP], Georg Kochs[SUP] 20 21 [/SUP], Masayuki Shimojima[SUP] 10 [/SUP], Yi-Shuian Huang[SUP] 22 23 [/SUP], Andreas Pichlmair[SUP] 24 25 [/SUP], Beate M Kümmerer[SUP] 9 26 [/SUP], Yoshihiro Sakoda[SUP] 2 3 [/SUP], Martin Schlee[SUP] 12 [/SUP], Linda Brunotte[SUP] 6 27 [/SUP], Christa E Müller[SUP] 8 [/SUP], Manabu Igarashi[SUP] 2 28 [/SUP], Hiroki Kato[SUP] 1 [/SUP]
Affiliations
- PMID: 36758070
- DOI: 10.1126/science.add0875
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.