tetano
Editor, Senior Moderator
Sci Rep. 2019 Mar 5;9(1):3466. doi: 10.1038/s41598-019-39683-4.
[h=1]Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil.[/h] Taniguchi K[SUP]1,[/SUP][SUP]2[/SUP], Ando Y[SUP]1[/SUP], Nobori H[SUP]1,[/SUP][SUP]3[/SUP], Toba S[SUP]1,[/SUP][SUP]3[/SUP], Noshi T[SUP]1[/SUP], Kobayashi M[SUP]1,[/SUP][SUP]4[/SUP], Kawai M[SUP]1[/SUP], Yoshida R[SUP]1[/SUP], Sato A[SUP]1,[/SUP][SUP]3[/SUP], Shishido T[SUP]5[/SUP], Naito A[SUP]1[/SUP], Matsuno K[SUP]2,[/SUP][SUP]6[/SUP], Okamatsu M[SUP]2[/SUP], Sakoda Y[SUP]2,[/SUP][SUP]6[/SUP], Kida H[SUP]3,[/SUP][SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
PMID: 30837531 PMCID: PMC6401108 DOI: 10.1038/s41598-019-39683-4
Free PMC Article
[h=1]Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil.[/h] Taniguchi K[SUP]1,[/SUP][SUP]2[/SUP], Ando Y[SUP]1[/SUP], Nobori H[SUP]1,[/SUP][SUP]3[/SUP], Toba S[SUP]1,[/SUP][SUP]3[/SUP], Noshi T[SUP]1[/SUP], Kobayashi M[SUP]1,[/SUP][SUP]4[/SUP], Kawai M[SUP]1[/SUP], Yoshida R[SUP]1[/SUP], Sato A[SUP]1,[/SUP][SUP]3[/SUP], Shishido T[SUP]5[/SUP], Naito A[SUP]1[/SUP], Matsuno K[SUP]2,[/SUP][SUP]6[/SUP], Okamatsu M[SUP]2[/SUP], Sakoda Y[SUP]2,[/SUP][SUP]6[/SUP], Kida H[SUP]3,[/SUP][SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
PMID: 30837531 PMCID: PMC6401108 DOI: 10.1038/s41598-019-39683-4
Free PMC Article