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

• Published in: Scientific reports Vol. 9; no. 1; p. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.03.2019; Nature Publishing Group
• Subjects: 13/106; 13/21; 631/154/436/2388; 64/60; 692/700/565/1436/2774; Amino acids; Animals; Antiviral Agents - pharmacology; Antiviral drugs; Avian flu; Cell culture; Cytokines - biosynthesis; Dibenzothiepins; Disease Models, Animal; Ducks; Endonuclease; Endonucleases - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Global health; Humanities and Social Sciences; Humans; Inflammation Mediators - metabolism; Influenza; Influenza A; Influenza A Virus, H7N9 Subtype - drug effects; Influenza A Virus, H7N9 Subtype - enzymology; Influenza in Birds - drug therapy; Influenza in Birds - virology; Influenza, Human - drug therapy; Influenza, Human - metabolism; Influenza, Human - virology; Mice; Morpholines; multidisciplinary; Oral administration; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - virology; Oxazines - pharmacology; Pyridines - pharmacology; Pyridones; Science; Science (multidisciplinary); Thiepins - pharmacology; Triazines - pharmacology; Viral Load; Virus Replication - drug effects; Viruses
• DOI: 10.1038/s41598-019-39683-4
• ISSN: 2045-2322

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.