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

Toba, Shinsuke; Sato, Akihiko; Kawai, Makoto; Taoda, Yoshiyuki; Unoh, Yuto; Kusakabe, Shinji; Nobori, Haruaki; Uehara, Shota; Uemura, Kentaro; Taniguchi, Keiichi; Kobayashi, Masanori; Noshi, Takeshi; Yoshida, Ryu; Naito, Akira; Shishido, Takao; Maruyama, Junki; Paessler, Slobodan; Carr, Michael J.; Hall, William W.; Yoshimatsu, Kumiko; Arikawa, Jiro; Matsuno, Keita; Sakoda, Yoshihiro; Sasaki, Michihito; Orba, Yasuko; Sawa, Hirofumi; Kida, Hiroshi

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

Toba, Shinsuke; Sato, Akihiko; Kawai, Makoto et al.

Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(36), e2206104119

Permalink : https://hdl.handle.net/2115/87810

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アクセス権	open access
URI	https://hdl.handle.net/2115/87810
タイトル	Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses
著者	Toba, Shinsuke ; Sato, Akihiko ; Kawai, Makoto ; Taoda, Yoshiyuki ; Unoh, Yuto ; Kusakabe, Shinji ; Nobori, Haruaki ; Uehara, Shota ; Uemura, Kentaro ; Taniguchi, Keiichi ; Kobayashi, Masanori ; Noshi, Takeshi ; Yoshida, Ryu ; Naito, Akira ; Shishido, Takao ; Maruyama, Junki ; Paessler, Slobodan ; Carr, Michael J. ; Hall, William W. ; Yoshimatsu, Kumiko ; Arikawa, Jiro ; Matsuno, Keita ; Sakoda, Yoshihiro ; Sasaki, Michihito ; Orba, Yasuko ; Sawa, Hirofumi ; Kida, Hiroshi
著者名 Toba, Shinsuke
著者名 Sato, Akihiko
著者名 Kawai, Makoto
著者名 Taoda, Yoshiyuki
著者名 Unoh, Yuto
著者名 Kusakabe, Shinji
著者名 Nobori, Haruaki
著者名 Uehara, Shota
著者名 Uemura, Kentaro
著者名 Taniguchi, Keiichi
著者名 Kobayashi, Masanori
著者名 Noshi, Takeshi
著者名 Yoshida, Ryu
著者名 Naito, Akira
著者名 Shishido, Takao
著者名 Maruyama, Junki
著者名 Paessler, Slobodan
e-Rad_Researcher 70769588 著者名 Carr, Michael J.
著者名 Hall, William W.
e-Rad_Researcher 90220722 著者名 Yoshimatsu, Kumiko
e-Rad_Researcher 10142704 著者名 Arikawa, Jiro
e-Rad_Researcher 40753306 著者名 Matsuno, Keita
e-Rad_Researcher 40333637 著者名 Sakoda, Yoshihiro
e-Rad_Researcher 70609403 著者名 Sasaki, Michihito
e-Rad_Researcher 60507169 著者名 Orba, Yasuko
e-Rad_Researcher 30292006 著者名 Sawa, Hirofumi
e-Rad_Researcher 10109506 著者名 Kida, Hiroshi
言語	英語
キーワード	Antiviral compounds
	Cap-dependent endonuclease
	Bunyavirus
発行日	2022-08-29
出版者	National Academy of Sciences
収録物名	Proceedings of the National Academy of Sciences of the United States of America
巻(号)	119(36)
ページ	e2206104119
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
PISSN	0027-8424
EISSN	1091-6490
NCID	AA10808769
関連情報	PMID 36037386
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1073/pnas.2206104119