2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses-Reference-Cited by-同舟云学术

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

Published:2023-10-13 Issue:42 Volume:120 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Uemura Kentaro¹²³⁴^ORCID,Nobori Haruaki²^ORCID,Sato Akihiko²³⁵^ORCID,Toba Shinsuke²³^ORCID,Kusakabe Shinji²³^ORCID,Sasaki Michihito³^ORCID,Tabata Koshiro³^ORCID,Matsuno Keita⁶⁷⁸^ORCID,Maeda Naoyoshi⁹,Ito Shiori¹^ORCID,Tanaka Mayu¹,Anraku Yuki¹,Kita Shunsuke¹,Ishii Mayumi¹⁰,Kanamitsu Kayoko¹⁰^ORCID,Orba Yasuko³⁸,Matsuura Yoshiharu⁴^ORCID,Hall William W.⁸¹¹¹²^ORCID,Sawa Hirofumi³⁵⁷⁸¹²^ORCID,Kida Hiroshi¹³^ORCID,Matsuda Akira⁹,Maenaka Katsumi¹⁵⁹¹⁴^ORCID

Affiliation:

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.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

MEXT | Japan Science and Technology Agency

Takeda Science Foundation

Atlantic Philanthropies

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2304139120

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