Verdinexor, a Novel Selective Inhibitor of Nuclear Export, Reduces Influenza A Virus Replication In Vitro and In Vivo
Verdinexor, a Novel Selective Inhibitor of Nuclear Export, Reduces Influenza A Virus Replication In Vitro and In Vivo
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DOI：
10.1128/jvi.01774-14
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发表时间：
2014-09-01
影响因子：
5.4
通讯作者：
Tripp, Ralph A.
中科院分区：
文献类型：
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作者：
Perwitasari, Olivia;Johnson, Scott;Tripp, Ralph A.
流感是一个全球性的健康问题，导致死亡、发病和经济损失。已有针对流感病毒的化疗药物；然而，耐药菌株的迅速出现是很常见的。治疗性靶向被流感病毒劫持的宿主蛋白以促进复制是减少耐药性发展的抗病毒策略。流感病毒核糖核蛋白 (vRNP) 从受感染细胞的核输出已被证明是由输出蛋白 1 (XPO1) 与连接到 vRNP 的病毒核输出蛋白相互作用介导的。 RNA 干扰筛选已将 XPO1 确定为宿主流感原因子，其中 XPO1 沉默会导致流感病毒复制减少。链霉菌代谢物 XPO1 抑制剂 leptomycin B (LMB) 已被证明可以限制流感病毒的体外复制；然而，LMB 在体内具有毒性，这使得它不适合用于治疗用途。在这项研究中，我们测试了一类新型口服小分子选择性核输出抑制剂的抗流感病毒活性，特别是 XPO1 拮抗剂 KPT-335 (verdinexor)。 Verdinexor 被证明能够有效、选择性地抑制 vRNP 输出，并在体外有效抑制各种甲型和乙型流感病毒株的复制，包括大流行性 H1N1 病毒、高致病性 H5N1 禽流感病毒和最近出现的 H7N9 病毒株。在体内，预防性和治疗性施用 verdinexor 可保护小鼠在受到流感病毒 A/California/04/09 或 A/Philippines/2/82-X79 攻击后免受疾病病理影响，并减少肺部病毒载量和促炎细胞因子表达，同时具有最小的毒性。这些研究表明 verdinexor 作为一种新型抗流感病毒治疗剂。重要性抗病毒药物是控制流感病毒的重要手段。然而，对目前批准的流感治疗药物已经产生了显着的耐药性。需要新的抗病毒方法来解决耐药性并减轻流感病毒相关疾病的负担。这项研究针对开发 verdinexor (KPT-335) 作为一种新型抗病毒药物进行了关键的临床前研究。 Verdinexor 阻断子代流感病毒基因组核输出，从而有效抑制病毒复制。 Verdinexor被发现可以限制多种甲型和乙型流感病毒株的复制，包括大流行性H1N1流感病毒株、高致病性H5N1禽流感病毒株和最近出现的H7N9流感病毒株。重要的是，预防性或治疗性口服 verdinexor 治疗除了限制肺部促炎细胞因子表达、病理和死亡外，还可以有效限制流感病毒感染小鼠的肺部病毒负荷。因此，这项研究证明 verdinexor 在体外和体内均能有效对抗流感病毒感染。
Influenza is a global health concern, causing death, morbidity, and economic losses. Chemotherapeutics that target influenza virus are available; however, rapid emergence of drug-resistant strains is common. Therapeutic targeting of host proteins hijacked by influenza virus to facilitate replication is an antiviral strategy to reduce the development of drug resistance. Nuclear export of influenza virus ribonucleoprotein (vRNP) from infected cells has been shown to be mediated by exportin 1 (XPO1) interaction with viral nuclear export protein tethered to vRNP. RNA interference screening has identified XPO1 as a host proinfluenza factor where XPO1 silencing results in reduced influenza virus replication. The Streptomyces metabolite XPO1 inhibitor leptomycin B (LMB) has been shown to limit influenza virus replication in vitro; however, LMB is toxic in vivo, which makes it unsuitable for therapeutic use. In this study, we tested the anti-influenza virus activity of a new class of orally available small-molecule selective inhibitors of nuclear export, specifically, the XPO1 antagonist KPT-335 (verdinexor). Verdinexor was shown to potently and selectively inhibit vRNP export and effectively inhibited the replication of various influenza virus A and B strains in vitro, including pandemic H1N1 virus, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain. In vivo, prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following a challenge with influenza virus A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral loads and proinflammatory cytokine expression, while having minimal toxicity. These studies show that verdinexor acts as a novel anti-influenza virus therapeutic agent.IMPORTANCEAntiviral drugs represent important means of influenza virus control. However, substantial resistance to currently approved influenza therapeutic drugs has developed. New antiviral approaches are required to address drug resistance and reduce the burden of influenza virus-related disease. This study addressed critical preclinical studies for the development of verdinexor (KPT-335) as a novel antiviral drug. Verdinexor blocks progeny influenza virus genome nuclear export, thus effectively inhibiting virus replication. Verdinexor was found to limit the replication of various strains of influenza A and B viruses, including a pandemic H1N1 influenza virus strain, a highly pathogenic H5N1 avian influenza virus strain, and a recently emerging H7N9 influenza virus strain. Importantly, oral verdinexor treatments, given prophylactically or therapeutically, were efficacious in limiting lung virus burdens in influenza virus-infected mice, in addition to limiting lung proinflammatory cytokine expression, pathology, and death. Thus, this study demonstrated that verdinexor is efficacious against influenza virus infection in vitro and in vivo.