Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil

Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor...

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Bibliographic Details
Published in:Scientific reports 2019-03, Vol.9 (1), p.3466, Article 3466
Main Authors: Taniguchi, Keiichi, Ando, Yoshinori, Nobori, Haruaki, Toba, Shinsuke, Noshi, Takeshi, Kobayashi, Masanori, Kawai, Makoto, Yoshida, Ryu, Sato, Akihiko, Shishido, Takao, Naito, Akira, Matsuno, Keita, Okamatsu, Masatoshi, Sakoda, Yoshihiro, Kida, Hiroshi
Format: Article
Language:English
Subjects:
Amino acids
Antiviral drugs
Avian flu
Cell culture
Endonuclease
Influenza
Influenza A
Oral administration
Viruses
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Summary:Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro and in vivo. In cell culture, BXA at four nanomolar concentration achieved a 1.5-2.8 log reduction in virus titers of A(H7N9), including the NA-R292K mutant virus and highly pathogenic avian influenza viruses, whereas NA inhibitors or favipiravir required approximately 20-fold or higher concentrations to achieve the same levels of reduction. A(H7N9)-specific amino acid polymorphism at position 37, implicated in BXA binding to the PA endonuclease domain, did not impact on BXA susceptibility. In mice, oral administration of BXM at 5 and 50 mg/kg twice a day for 5 days completely protected from a lethal A/Anhui/1/2013 (H7N9) challenge, and reduced virus titers more than 2-3 log in the lungs. Furthermore, the potent therapeutic effects of BXM in mice were still observed when a higher virus dose was administered or treatment was delayed up to 48 hours post infection. These findings support further investigation of BXM for A(H7N9) treatment in humans.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-39683-4