In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit
| Autor: | Masatoshi Okamatsu, Keiichi Taniguchi, Masanori Kobayashi, Kayo Ishida, Takao Shishido, Keiko Baba, Yoshihiro Sakoda, Yukihiro Kushima, Tomokazu Yoshinaga, Mitsutaka Kitano, Akihiko Sato, Atsuko Yamamoto, Takeshi Noshi, Makoto Kawai, Hiroshi Kida, Kazunari Hattori, Akira Naito, Shinya Omoto, Ryu Yoshida, Takashi Hashimoto |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Dibenzothiepins Transcription Genetic Pyridines Pyridones Morpholines 030106 microbiology DNA Mutational Analysis Mutation Missense Microbial Sensitivity Tests Virus Replication Antiviral Agents Virus 03 medical and health sciences Viral Proteins Cytopathogenic Effect Viral Transcription (biology) Virology Drug Resistance Viral Oxazines Serial Passage Polymerase Cytopathic effect Pharmacology biology Chemistry Triazines Endonucleases RNA-Dependent RNA Polymerase Molecular biology In vitro Reverse genetics Reverse Genetics Influenza B virus 030104 developmental biology Viral replication Influenza A virus biology.protein Thiepins Neuraminidase |
| Zdroj: | Antiviral research. 160 |
| ISSN: | 1872-9096 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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