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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Keiichi Taniguchi, Yoshinori Ando, Haruaki Nobori, Shinsuke Toba, Takeshi Noshi, Masanori Kobayashi, Makoto Kawai, Ryu Yoshida, Akihiko Sato, Takao Shishido, Akira Naito, Keita Matsuno, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida

ABSTRACT

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. More... »

PAGES

3466

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41598-019-39683-4

    DOI

    http://dx.doi.org/10.1038/s41598-019-39683-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112543985

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30837531


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