2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses

  • Proc Natl Acad Sci U S A. 2023 Oct 17;120(42):e2304139120. doi: 10.1073/pnas.2304139120.
Kentaro Uemura  1  2  3  4 ,  Haruaki Nobori  2 ,  Akihiko Sato  2  3  5 ,  Shinsuke Toba  2  3 ,  Shinji Kusakabe  2  3 ,  Michihito Sasaki  3 ,  Koshiro Tabata  3 ,  Keita Matsuno  6  7  8 ,  Naoyoshi Maeda  9 ,  Shiori Ito  1 ,  Mayu Tanaka  1 ,  Yuki Anraku  1 ,  Shunsuke Kita  1 ,  Mayumi Ishii  10 ,  Kayoko Kanamitsu  10 ,  Yasuko Orba  3  8 ,  Yoshiharu Matsuura  4 ,  William W Hall  8  11  12 ,  Hirofumi Sawa  3  5  7  8  12 ,  Hiroshi Kida  13 ,  Akira Matsuda  9 ,  Katsumi Maenaka  1  5  9  14
Affiliations
  • 1. Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
  • 2. Drug Discovery and Disease Research Laboratory, Shionogi & Co. Ltd., Osaka 561-0825, Japan.
  • 3. Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
  • 4. Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan.
  • 5. Institute for Vaccine Research and Development, Hokkaido University, Sapporo 001-0021, Japan.
  • 6. Unit of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
  • 7. One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan.
  • 8. International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
  • 9. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
  • 10. Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, Tokyo 113-0033, Japan.
  • 11. National Virus Reference Laboratory, School of Medicine, University College of Dublin, Dublin D04, Ireland.
  • 12. Global Virus Network, Baltimore, MD 21201.
  • 13. Laboratory for Biologics Development, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan.
  • 14. Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Sapporo 060-0812, Japan.
PMID: 37831739 DOI: 10.1073/pnas.2304139120
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically Dengue Virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many Other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as a broad-spectrum Antiviral ribonucleoside analogue that exhibited Antiviral activity against several positive-sense single-stranded RNA (ssRNA+) viruses, such as DENV, SARS-CoV-2, and its variants of concern, including the currently circulating Omicron subvariants. s2U inhibits RNA synthesis catalyzed by viral RNA-dependent RNA polymerase, thereby reducing viral RNA replication, which improved the survival rate of mice infected with DENV2 or SARS-CoV-2 in our animal models. Our findings demonstrate that s2U is a potential broad-spectrum Antiviral agent not only against DENV and SARS-CoV-2 but Other ssRNA+ viruses.

Keywords
RNA-dependent RNA polymerase; SARS-CoV-2; antiviral; dengue virus; positive-strand RNA viruses.
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