Wei Xiafei, Zhou Yuzheng, Shen Xiaotong, Fan Lujie, Liu Donglan, Gao Xiang, Zhou Jian, Wu Yezi, Li Yunfei, Feng Wei, Zhang Zheng
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen 518112, China.
Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 511495, China.
Acta Pharm Sin B. 2024 Jun;14(6):2505-2519. doi: 10.1016/j.apsb.2024.03.009. Epub 2024 Mar 12.
The nucleocapsid protein (NP) plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life. Despite its vital role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assembly and host inflammatory response, it remains an unexplored target for drug development. In this study, we identified a small-molecule compound (ciclopirox) that promotes NP degradation using an FDA-approved library and a drug-screening cell model. Ciclopirox significantly inhibited SARS-CoV-2 replication both and by inducing NP degradation. Ciclopirox induced abnormal NP aggregation through indirect interaction, leading to the formation of condensates with higher viscosity and lower mobility. These condensates were subsequently degraded the autophagy-lysosomal pathway, ultimately resulting in a shortened NP half-life and reduced NP expression. Our results suggest that NP is a potential drug target, and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
核衣壳蛋白（NP）在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）复制过程中起着关键作用，是半衰期较长且含量最丰富的结构蛋白。尽管其在SARS-CoV-2组装和宿主炎症反应中发挥着重要作用，但它仍是药物研发领域尚未被探索的靶点。在本研究中，我们使用美国食品药品监督管理局（FDA）批准的化合物库和药物筛选细胞模型，鉴定出一种促进NP降解的小分子化合物（环吡酮）。环吡酮通过诱导NP降解，在体外和体内均显著抑制了SARS-CoV-2的复制。环吡酮通过间接相互作用诱导NP异常聚集，导致形成具有更高粘度和更低流动性的凝聚物。这些凝聚物随后通过自噬-溶酶体途径被降解，最终导致NP半衰期缩短和NP表达减少。我们的研究结果表明，NP是一个潜在的药物靶点，环吡酮在对抗SARS-CoV-2复制的进一步开发中具有巨大潜力。
