Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication PMID: 36758070

ADC Targets in Oncology

2026-04-10

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

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.