Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases

  • EMBO J. 2022 Sep 1;41(17):e111608. doi: 10.15252/embj.2022111608.
Valter Bergant  #  1 ,  Shintaro Yamada  #  2 ,  Vincent Grass  #  1 ,  Yuta Tsukamoto  #  2 ,  Teresa Lavacca  1 ,  Karsten Krey  1 ,  Maria-Teresa Mühlhofer  1 ,  Sabine Wittmann  3 ,  Armin Ensser  3 ,  Alexandra Herrmann  3 ,  Anja Vom Hemdt  4 ,  Yuriko Tomita  5 ,  Shutoku Matsuyama  5 ,  Takatsugu Hirokawa  6  7  8 ,  Yiqi Huang  1 ,  Antonio Piras  1 ,  Constanze A Jakwerth  9 ,  Madlen Oelsner  9 ,  Susanne Thieme  10 ,  Alexander Graf  10 ,  Stefan Krebs  10 ,  Helmut Blum  10 ,  Beate M Kümmerer  4  11 ,  Alexey Stukalov  1 ,  Carsten B Schmidt-Weber  9 ,  Manabu Igarashi  12  13 ,  Thomas Gramberg  3 ,  Andreas Pichlmair  1  14 ,  Hiroki Kato  2
Affiliations
  • 1. Institute of Virology, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
  • 2. Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn (UKB), Bonn, Germany.
  • 3. Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
  • 4. Institute of Virology, Medical Faculty, University of Bonn, Bonn, Germany.
  • 5. Department of Virology III, National Institute of Infectious Diseases (NIID), Tokyo, Japan.
  • 6. Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
  • 7. Division of Biomedical Science, University of Tsukuba, Tsukuba, Japan.
  • 8. Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 9. Center for Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Center Munich, German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, Munich, Germany.
  • 10. Laboratory for functional genome analysis (LAFUGA), Gene Centre, Ludwig Maximilian University of Munich (LMU), Munich, Germany.
  • 11. German Center for Infection Research (DZIF), Bonn-Cologne Partner Site, Bonn, Germany.
  • 12. International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
  • 13. Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
  • 14. German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
  • # Contributed equally.
PMID: 35833542 DOI: 10.15252/embj.2022111608
Abstract

The SARS-CoV-2 Infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed Antiviral drugs against both viral and host Enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show Antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is Antiviral in in vitro, in ex vivo, and in a mouse Infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.

Keywords
COVID-19; SARS-CoV-2; antivirals; host-directed; methyltransferase.
Products