期刊
ANTIVIRAL RESEARCH
卷 160, 期 -, 页码 109-117出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2018.10.008
关键词
Influenza virus; Cap-dependent endonuclease; Baloxavir marboxil; Baloxavir acid
资金
- Shionogi & Co., Ltd., Japan
Cap-dependent endonuclease (CEN) resides in the PA subunit of the influenza virus and mediates the critical cap-snatching step of viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe in vitro characterization of a novel CEN inhibitor, baloxavir acid (BXA), the active form of baloxavir marboxil (BXM). BXA inhibits viral RNA transcription via selective inhibition of CEN activity in enzymatic assays, and inhibits viral replication in infected cells without cytotoxicity in cytopathic effect assays. The antiviral activity of BXA is also confirmed in yield reduction assays with seasonal type A and B viruses, including neuraminidase inhibitor-resistant strains. Furthermore, BXA shows broad potency against various subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). Additionally, serial passages of the viruses in the presence of BXA result in isolation of PA/I38T variants with reduced BXA susceptibility. Phenotypic and genotypic analyses with reverse genetics demonstrate the mechanism of BXA action via CEN inhibition in infected cells. These results reveal the in vitro characteristics of BXA and support clinical use of BXM to treat influenza.
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