RT Journal Article
SR Electronic
T1 A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.11.986836
DO 10.1101/2020.03.11.986836
A1 Yiyue Ge
A1 Tingzhong Tian
A1 Suling Huang
A1 Fangping Wan
A1 Jingxin Li
A1 Shuya Li
A1 Hui Yang
A1 Lixiang Hong
A1 Nian Wu
A1 Enming Yuan
A1 Lili Cheng
A1 Yipin Lei
A1 Hantao Shu
A1 Xiaolong Feng
A1 Ziyuan Jiang
A1 Ying Chi
A1 Xiling Guo
A1 Lunbiao Cui
A1 Liang Xiao
A1 Zeng Li
A1 Chunhao Yang
A1 Zehong Miao
A1 Haidong Tang
A1 Ligong Chen
A1 Hainian Zeng
A1 Dan Zhao
A1 Fengcai Zhu
A1 Xiaokun Shen
A1 Jianyang Zeng
YR 2020
UL http://biorxiv.org/content/early/2020/03/12/2020.03.11.986836.abstract
AB The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both 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. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. 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 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.