Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Institute of Translational Pharmacology, CNR, Rome, Italy.
Cell Mol Life Sci. 2022 Apr 7;79(5):227. doi: 10.1007/s00018-022-04246-w.
SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.
SARS-CoV-2 是 COVID-19 的病原体，引发了一场前所未有的全球卫生危机。SARS-CoV-2 刺突蛋白是一种锚定在表面的三聚体 I 型融合糖蛋白，对病毒进入至关重要，是开发能够阻断病毒入侵的疫苗和治疗药物的关键靶点。能够促进病毒传播并可能影响疫苗效力的 SARS-CoV-2 刺突变异株的出现，凸显了确定 COVID-19 治疗新型抗病毒策略的必要性。在这里，我们证明硝唑尼特是一种具有广泛抗病毒活性的抗寄生虫药物，可干扰 SARS-CoV-2 刺突蛋白的成熟，阻碍其在末端糖苷酶 H 敏感阶段的末端糖基化。通过工程化多种 SARS-CoV-2 变体假病毒并利用定量细胞-细胞融合测定，我们表明硝唑尼特诱导的刺突蛋白修饰会阻碍病毒粒子的感染力以及刺突蛋白驱动的肺细胞-细胞融合，这是 COVID-19 病理学的一个关键特征。硝唑尼特对原始的 SARS-CoV-2 武汉刺突蛋白和不同的新兴变异株（包括关注的 Delta 变异株）同样有效，可能是对抗 COVID-19 感染的有用工具。
