| 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 |
| Bunyavirus |
| 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. |
| Rights: | https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/87810 |
| 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)
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