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.
Highlights
Influenza pandemics arise when novel reassortant influenza A viruses acquire zoonotic potential and adapt to enable efficient and widespread human-to-human infection[1]
Viruses typically harbor a polymorphic alanine to serine substitution at residue 37 in the PA (A37S)[36,37], which is involved in baloxavir acid (BXA) binding in the endonuclease domain (Table 1)[32,38]
We evaluated the in vitro antiviral activity of BXA against influenza A(H7N9) viruses, including highly pathogenic avian influenza viruses, and the therapeutic effect of Baloxavir marboxil (BXM) in vivo in murine lethal models employing influenza A(H7N9) virus
Summary
Influenza pandemics arise when novel reassortant influenza A viruses acquire zoonotic potential and adapt to enable efficient and widespread human-to-human infection[1]. Antiviral medications are of critical importance to reduce the burden of disease caused by A(H7N9) and the U.S Centers for Disease Control and Prevention (CDC) recommends the use of antivirals for treatment of all hospitalized cases of human infection with novel influenza A viruses associated with severe disease[13]. The active center of CEN is highly conserved across seasonal, pandemic, and highly pathogenic avian influenza viruses[26,28], indicating that CEN inhibitors have the potential to be broadly-active anti-influenza drugs[28,29,30]. We report the antiviral activities of BXA and BXM against human influenza A(H7N9) viruses, including highly pathogenic avian influenza viruses. Our findings support further investigation of the therapeutic efficacy of BXM treatment in A(H7N9)-infected patients
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