Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo.
Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo.
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DOI：
10.1016/j.antiviral.2021.105115
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发表时间：
2021-08
影响因子：
7.6
通讯作者：
Landesman Y
中科院分区：
文献类型：
--
作者：
Kashyap T;Murray J;Walker CJ;Chang H;Tamir S;Hou B;Shacham S;Kauffman MG;Tripp RA;Landesman Y
由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的2019新型冠状病毒病（COVID-19）是最近全球大流行的原因。核输出蛋白（XPO 1）在SARS冠状病毒蛋白质（包括ORF 3b、ORF 9 b和核衣壳）的输出中具有直接作用。抑制XPO 1可诱导抗炎、抗病毒和抗氧化途径。Selinexor是FDA批准的XPO 1抑制剂。通过生物信息学分析，我们预测了ACE-2蛋白中的核输出序列，并通过体外试验证实，用selinexor抑制XPO 1可诱导ACE-2的核定位。赛林克斯的给药在体外可抑制病毒感染，并具有治疗作用。在COVID-19的雪貂模型中，selinexor治疗降低了肺部的病毒载量，并在体内保护了鼻甲和肺部的组织损伤。我们的研究表明，selinexor下调了促炎细胞因子IL-1β、IL-6、IL-10、IFN-γ、TNF-α和GMCSF，这些细胞因子通常与COVID-19患者中观察到的细胞因子风暴相关。我们的研究结果表明，核输出对于SARS-CoV-2感染和COVID-19病理学至关重要，并表明通过selinexor抑制XPO 1可能是一种可行的抗病毒治疗选择。一个示意性模型证明了抑制核输出如何通过以下方式保护细胞免受SARS-CoV-2感染：减少ACE-2的膜呈递，阻断宿主蛋白GLTSCR 2的细胞质穿梭（Wang et al.，2016），和隔离病毒蛋白ORF 3b（Freundt et al.，2009; Konno等人，2020）、ORF 9 b（Moshynskyy等人，2007; Sharma等人，2011年; Jiang等人，2020）和核衣壳蛋白（Timani等人，2005; You等人，2007年; Li等人，2020年，在核。这允许先天免疫应答的激活和I型干扰素的产生。
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways. Selinexor is an FDA-approved XPO1 inhibitor. Through bioinformatics analysis, we predicted nuclear export sequences in the ACE-2 protein and confirmed by in vitro testing that inhibition of XPO1 with selinexor induces nuclear localization of ACE-2. Administration of selinexor inhibited viral infection prophylactically as well as therapeutically in vitro. In a ferret model of COVID-19, selinexor treatment reduced viral load in the lungs and protected against tissue damage in the nasal turbinates and lungs in vivo. Our studies demonstrated that selinexor downregulated the pro-inflammatory cytokines IL-1β, IL-6, IL-10, IFN-γ, TNF-α, and GMCSF, commonly associated with the cytokine storm observed in COVID-19 patients. Our findings indicate that nuclear export is critical for SARS-CoV-2 infection and for COVID-19 pathology and suggest that inhibition of XPO1 by selinexor could be a viable anti-viral treatment option. A schematic model demonstrates how inhibition of nuclear export protects cells from SARS-CoV-2 infection by: reducing membranal presentation of ACE-2, blocking the cytoplasmic shuttling of the host protein GLTSCR2, (Wang et al., 2016), and sequestering the viral proteins ORF3b (Freundt et al., 2009; Konno et al., 2020), ORF9b (Moshynskyy et al., 2007; Sharma et al., 2011; Jiang et al., 2020), and the nucleocapsid protein (Timani et al., 2005; You et al., 2007; Li et al., 2020) in the nucleus. This allows for the activation of the innate immune response and the production of the type I interferons.