Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, China.
NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, China.
Signal Transduct Target Ther. 2021 Apr 24;6(1):165. doi: 10.1038/s41392-021-00568-6.
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的全球传播需要紧急寻找有效的治疗方法来治疗 2019 年冠状病毒病（COVID-19）。在这项研究中，我们开发了一种综合药物再定位框架，充分利用机器学习和统计分析方法，系统地整合和挖掘大规模的知识图谱、文献和转录组数据，以发现针对 SARS-CoV-2 的潜在药物候选物。我们的计算机筛选随后进行的湿实验室验证表明，一种多聚 ADP-核糖聚合酶 1（PARP1）抑制剂 CVL218，目前正在进行 I 期临床试验，可能被重新用于治疗 COVID-19。我们的体外实验表明，CVL218 可以有效抑制 SARS-CoV-2 的复制，而没有明显的细胞病变效应。此外，我们还表明，CVL218 可以与 SARS-CoV-2 的核衣壳（N）蛋白相互作用，并能够抑制 LPS 诱导的几种与预防 SARS-CoV-2 感染引起的免疫病理学相关的炎症细胞因子的产生。
