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Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses

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Title: Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses
Authors: Toba, Shinsuke Browse this author
Sato, Akihiko Browse this author
Kawai, Makoto Browse this author
Taoda, Yoshiyuki Browse this author
Unoh, Yuto Browse this author
Kusakabe, Shinji Browse this author
Nobori, Haruaki Browse this author
Uehara, Shota Browse this author
Uemura, Kentaro Browse this author
Taniguchi, Keiichi Browse this author
Kobayashi, Masanori Browse this author
Noshi, Takeshi Browse this author
Yoshida, Ryu Browse this author
Naito, Akira Browse this author
Shishido, Takao Browse this author
Maruyama, Junki Browse this author
Paessler, Slobodan Browse this author
Carr, Michael J. Browse this author →KAKEN DB
Hall, William W. Browse this author
Yoshimatsu, Kumiko Browse this author →KAKEN DB
Arikawa, Jiro Browse this author →KAKEN DB
Matsuno, Keita Browse this author →KAKEN DB
Sakoda, Yoshihiro Browse this author →KAKEN DB
Sasaki, Michihito Browse this author →KAKEN DB
Orba, Yasuko Browse this author →KAKEN DB
Sawa, Hirofumi Browse this author →KAKEN DB
Kida, Hiroshi Browse this author →KAKEN DB
Keywords: Antiviral compounds
Cap-dependent endonuclease
Issue Date: 29-Aug-2022
Publisher: National Academy of Sciences
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 119
Issue: 36
Start Page: e2206104119
Publisher DOI: 10.1073/pnas.2206104119
PMID: 36037386
Abstract: Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.
Type: article
Appears in Collections:人獣共通感染症国際共同研究所 (International Institute for Zoonosis Control) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐々木 道仁

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