Shionogi & Co., Ltd., Osaka, Japan.
Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Sci Rep. 2019 Mar 5;9(1):3466. doi: 10.1038/s41598-019-39683-4.
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.
人感染禽流感 H7N9 病毒对全球健康构成严重威胁；然而，治疗选择有限。在这里，我们展示了巴洛沙韦酸（BXA）及其前药巴洛沙韦马波西利（BXM）对 H7N9 的体外和体内抑制作用，BXA 是一种首创的帽依赖性内切酶抑制剂。在细胞培养中，BXA 在 4 纳摩尔浓度下可使 H7N9 病毒滴度降低 1.5-2.8 对数，包括 NA-R292K 突变病毒和高致病性禽流感病毒，而 NA 抑制剂或法匹拉韦需要约 20 倍或更高浓度才能达到相同的降低水平。PA 内切酶结构域结合的 BXA 结合位点处的 H7N9 特异性氨基酸多态性不影响 BXA 的敏感性。在小鼠中，每天口服 BXM 5 和 50mg/kg，连续 5 天，可完全预防致死性 A/Anhui/1/2013（H7N9）挑战，并且在肺部使病毒滴度降低 2-3 个对数以上。此外，当给予更高剂量的病毒或感染后延迟至 48 小时以上开始治疗时，BXM 在小鼠中的强效治疗效果仍然存在。这些发现支持进一步研究 BXM 用于人类 H7N9 治疗。
