In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit

Publication date: Available online 11 October 2018Source: Antiviral ResearchAuthor(s): Takeshi Noshi, Mitsutaka Kitano, Keiichi Taniguchi, Atsuko Yamamoto, Shinya Omoto, Keiko Baba, Takashi Hashimoto, Kayo Ishida, Yukihiro Kushima, Kazunari Hattori, Makoto Kawai, Ryu Yoshida, Masanori Kobayashi, Tomokazu Yoshinaga, Akihiko Sato, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Takao Shishido, Akira NaitoAbstractCap-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...
Source: Antiviral Therapy - Category: Virology Source Type: research