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A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

Yiyue Ge, Tingzhong Tian, Suling Huang, Fangping Wan, Jingxin Li, Shuya Li, Hui Yang, Lixiang Hong, Nian Wu, Enming Yuan, Lili Cheng, Yipin Lei, Hantao Shu, Xiaolong Feng, Ziyuan Jiang, Ying Chi, Xiling Guo, Lunbiao Cui, Liang Xiao, Zeng Li, Chunhao Yang, Zehong Miao, Haidong Tang, Ligong Chen, Hainian Zeng, Dan Zhao, Fengcai Zhu, Xiaokun Shen, Jianyang Zeng
doi: https://doi.org/10.1101/2020.03.11.986836
Yiyue Ge
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Tingzhong Tian
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Suling Huang
3Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Fangping Wan
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Jingxin Li
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Shuya Li
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Hui Yang
11Silexon AI Technology Co., Ltd., Nanjing, Jiangsu Province, 210033, China.
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Lixiang Hong
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Nian Wu
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Enming Yuan
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Lili Cheng
4School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
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Yipin Lei
11Silexon AI Technology Co., Ltd., Nanjing, Jiangsu Province, 210033, China.
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Hantao Shu
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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Xiaolong Feng
6School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430074, China.
7Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China.
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Ziyuan Jiang
5Department of Automation, Tsinghua University, Beijing, 100084, China.
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Ying Chi
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Xiling Guo
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Lunbiao Cui
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
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Liang Xiao
10Convalife (Shanghai) Co., Ltd., Shanghai, 201203, China.
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Zeng Li
10Convalife (Shanghai) Co., Ltd., Shanghai, 201203, China.
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Chunhao Yang
3Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Zehong Miao
3Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Haidong Tang
4School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
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Ligong Chen
4School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
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Hainian Zeng
11Silexon AI Technology Co., Ltd., Nanjing, Jiangsu Province, 210033, China.
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Dan Zhao
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
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  • For correspondence: zhaodan2018@tsinghua.edu.cn jszfc@vip.sina.com steve.shen@convalife.com zengjy321@tsinghua.edu.cn
Fengcai Zhu
2NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, 210009, China.
8Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu Province, 210009, China.
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  • For correspondence: zhaodan2018@tsinghua.edu.cn jszfc@vip.sina.com steve.shen@convalife.com zengjy321@tsinghua.edu.cn
Xiaokun Shen
10Convalife (Shanghai) Co., Ltd., Shanghai, 201203, China.
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  • For correspondence: zhaodan2018@tsinghua.edu.cn jszfc@vip.sina.com steve.shen@convalife.com zengjy321@tsinghua.edu.cn
Jianyang Zeng
1Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, 100084, China.
9MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, 100084, China.
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  • For correspondence: zhaodan2018@tsinghua.edu.cn jszfc@vip.sina.com steve.shen@convalife.com zengjy321@tsinghua.edu.cn
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Abstract

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.

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Posted March 12, 2020.
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A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
Yiyue Ge, Tingzhong Tian, Suling Huang, Fangping Wan, Jingxin Li, Shuya Li, Hui Yang, Lixiang Hong, Nian Wu, Enming Yuan, Lili Cheng, Yipin Lei, Hantao Shu, Xiaolong Feng, Ziyuan Jiang, Ying Chi, Xiling Guo, Lunbiao Cui, Liang Xiao, Zeng Li, Chunhao Yang, Zehong Miao, Haidong Tang, Ligong Chen, Hainian Zeng, Dan Zhao, Fengcai Zhu, Xiaokun Shen, Jianyang Zeng
bioRxiv 2020.03.11.986836; doi: https://doi.org/10.1101/2020.03.11.986836
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A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
Yiyue Ge, Tingzhong Tian, Suling Huang, Fangping Wan, Jingxin Li, Shuya Li, Hui Yang, Lixiang Hong, Nian Wu, Enming Yuan, Lili Cheng, Yipin Lei, Hantao Shu, Xiaolong Feng, Ziyuan Jiang, Ying Chi, Xiling Guo, Lunbiao Cui, Liang Xiao, Zeng Li, Chunhao Yang, Zehong Miao, Haidong Tang, Ligong Chen, Hainian Zeng, Dan Zhao, Fengcai Zhu, Xiaokun Shen, Jianyang Zeng
bioRxiv 2020.03.11.986836; doi: https://doi.org/10.1101/2020.03.11.986836

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