1. Academic Validation
  2. Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

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

Affiliations

  • 1 Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 2 International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  • 3 Laboratory of Microbiology, Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
  • 4 Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
  • 5 One Health Research Center, Hokkaido University, Sapporo, Hokkaido, Japan.
  • 6 Institute of Virology Muenster, Westfaelische Wilhelms-University, Muenster, Germany.
  • 7 CiM-IMPRS, Westfaelische Wilhelms-University Muenster, International Max Planck Research School - Molecular Biomedicine, Muenster, Germany.
  • 8 PharmaCenter Bonn and Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany.
  • 9 Institute of Virology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 10 Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan.
  • 11 Institute of Innate Immunity, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 12 Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty, University Hospital Bonn, Bonn, Germany.
  • 13 Department of Oncology, Hematology, Rheumatology and Immune-Oncology, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 14 Institute of Immunology, Philipps-University Marburg, Marburg, Germany.
  • 15 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 16 Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
  • 17 Division of Biomedical Science, University of Tsukuba, Tsukuba, Japan.
  • 18 Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 19 Core Facility Nanobodies, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
  • 20 Institute of Virology, Medical Center, University of Freiburg, Freiburg, Germany.
  • 21 Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 22 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 23 Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.
  • 24 Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany.
  • 25 German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany.
  • 26 German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
  • 27 Interdisciplinary Center for Medical Research, Medical Faculty Muenster, Germany.
  • 28 Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan.
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.

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