文章基本信息

标题：Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses
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作者：Shinsuke Toba ; Akihiko Sato ; Makoto Kawai 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2206104119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Bunyaviruses, like influenza viruses, possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We identified the antibunyavirus compounds among influenza CEN inhibitors and identified specific structures involved in the inhibitory mechanism. These were 100- to 1,000-fold more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. Since effective compounds against other bunyaviruses including La Crosse virus, severe fever with thrombocytopenia syndrome virus, and hantavirus were also identified, we demonstrated the potential clinical utility of CEN inhibitors for the treatment of viral hemorrhagic diseases. 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.
关键词：enantiviral compoundscap-dependent endonucleasebunyavirus