Yang Chen, Yu Yanying, Peng Qi, Song Jingwei, Sun Bo, Shi Yi, Ding Qiang
School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Biosaf Health. 2024 Sep 3;6(5):270-278. doi: 10.1016/j.bsheal.2024.09.001. eCollection 2024 Oct.
Despite the availability of vaccines and antiviral treatments, the continued emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and breakthrough infections underscores the need for new, potent antiviral therapies. In a previous study, we established a transcription and replication-competent SARS-CoV-2 virus-like particle (trVLP) system that recapitulates the complete viral life cycle. In this study, we combined high-content screening (HCS) with the SARS-CoV-2 trVLP cell culture system, providing a powerful phenotype-oriented approach to assess the antiviral potential of compounds on a large scale. We screened a library of 3,200 natural compounds and identified drupacine as a potential candidate against SARS-CoV-2 infection. Furthermore, we utilized a SARS-CoV-2 replicon system to demonstrate that drupacine could inhibit viral genome transcription and replication. However, enzymatic assays revealed that the inhibition could not be attributed to conventional antiviral targets, such as the viral non-structural proteins nsp5 (MPro) or nsp12 (RdRp). In conclusion, our findings position drupacine as a promising antiviral candidate against SARS-CoV-2, providing a novel scaffold for developing anti-coronavirus disease 2019 therapeutics. Further investigation is required to pinpoint its precise target and mechanism of action.
尽管有疫苗和抗病毒治疗方法，但严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的持续出现和突破性感染凸显了新型强效抗病毒疗法的必要性。在先前的一项研究中，我们建立了一种具有转录和复制能力的SARS-CoV-2病毒样颗粒（trVLP）系统，该系统概括了完整的病毒生命周期。在本研究中，我们将高内涵筛选（HCS）与SARS-CoV-2 trVLP细胞培养系统相结合，提供了一种强大的以表型为导向的方法来大规模评估化合物的抗病毒潜力。我们筛选了一个包含3200种天然化合物的文库，并确定了drupacine作为一种抗SARS-CoV-2感染的潜在候选物。此外，我们利用SARS-CoV-2复制子系统证明了drupacine可以抑制病毒基因组的转录和复制。然而，酶学分析表明，这种抑制作用不能归因于传统的抗病毒靶点，如病毒非结构蛋白nsp5（MPro）或nsp12（RdRp）。总之，我们的研究结果将drupacine定位为一种有前景的抗SARS-CoV-2病毒候选物，为开发抗2019冠状病毒病治疗药物提供了一种新的支架。需要进一步研究以确定其精确的靶点和作用机制。
