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

Kentaro Uemura; Haruaki Nobori; Akihiko Sato; Shinsuke Toba; Shinji Kusakabe; Michihito Sasaki; Koshiro Tabata; Keita Matsuno; Naoyoshi Maeda; Shiori Ito; Mayu Tanaka; Yuki Anraku; Shunsuke Kita; Mayumi Ishii; Kayoko Kanamitsu; Yasuko Orba; Yoshiharu Matsuura; William W Hall; Hirofumi Sawa; Hiroshi Kida; Akira Matsuda; Katsumi Maenaka

doi:10.1073/pnas.2304139120

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. Epub 2023 Oct 13.

Authors

Kentaro Uemura^{1

2

3

4}, Haruaki Nobori², Akihiko Sato^{2

3

5}, Shinsuke Toba^{2

3}, Shinji Kusakabe^{2

3}, Michihito Sasaki³, Koshiro Tabata³, Keita Matsuno^{6

7

8}, Naoyoshi Maeda⁹, Shiori Ito¹, Mayu Tanaka¹, Yuki Anraku¹, Shunsuke Kita¹, Mayumi Ishii¹⁰, Kayoko Kanamitsu¹⁰, Yasuko Orba^{3

8}, Yoshiharu Matsuura⁴, William W Hall^{8

11

12}, Hirofumi Sawa^{3

5

7

8

12}, Hiroshi Kida¹³, Akira Matsuda⁹, 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology
Mice
Nucleosides* / pharmacology
Positive-Strand RNA Viruses*
RNA
SARS-CoV-2
Virus Replication

Substances

Nucleosides
2-thiouridine
Antiviral Agents
RNA