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

In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.
Antiviral Res. 2018 Oct 11;:
Authors: Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A
Abstract
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 ...

Source: Antiviral Research - October 11, 2018 Category: Virology Authors: Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A Tags: Antiviral Res Source Type: research