O'Keefe Sarah, Roboti Peristera, Duah Kwabena B, Zong Guanghui, Schneider Hayden, Shi Wei Q, High Stephen
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom.
Department of Chemistry, Ball State University, Muncie, Indiana 47306, USA.
bioRxiv. 2021 Jan 5:2020.11.24.390039. doi: 10.1101/2020.11.24.390039.
In order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2 the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation/insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum, antiviral agents.
为了产生其繁殖所必需的蛋白质，许多致病性人类病毒，包括导致COVID-19呼吸道疾病的病原体SARS-CoV-2，会征用宿主的生物合成机器和机制。三种主要结构蛋白，即刺突蛋白、包膜蛋白和膜蛋白，是在新病毒颗粒组装之前在受感染人类细胞的内质网（ER）中合成的几种SARS-CoV-2成分之一。因此，在内质网抑制膜蛋白合成是降低SARS-CoV-2和其他专性病毒病原体致病性的一种有吸引力的策略。利用一种系统，我们证明小分子抑制剂异波塞辛F（Ipom-F）能有效阻断Sec61介导的内质网膜转位/插入三种针对SARS-CoV-2感染的治疗性蛋白靶点；病毒刺突蛋白和ORF8蛋白以及宿主细胞质膜受体血管紧张素转换酶2。我们的研究结果突出了使用内质网蛋白转位抑制剂如Ipom-F作为靶向宿主的广谱抗病毒药物的潜力。
