1. Academic Validation
  2. An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

  • Signal Transduct Target Ther. 2021 Apr 24;6(1):165. doi: 10.1038/s41392-021-00568-6.
Yiyue Ge  # 1 2 Tingzhong Tian  # 1 2 Suling Huang  # 3 Fangping Wan  # 1 Jingxin Li  # 2 Shuya Li 1 Xiaoting Wang 4 Hui Yang 4 Lixiang Hong 1 Nian Wu 1 Enming Yuan 1 Yunan Luo 5 Lili Cheng 6 Chengliang Hu 6 Yipin Lei 4 Hantao Shu 1 Xiaolong Feng 7 8 Ziyuan Jiang 9 Yunfu Wu 10 Ying Chi 2 Xiling Guo 2 Lunbiao Cui 2 Liang Xiao 11 Zeng Li 11 Chunhao Yang 3 Zehong Miao 3 Ligong Chen 6 12 Haitao Li 13 Hainian Zeng 4 Dan Zhao 14 Fengcai Zhu 15 16 Xiaokun Shen 17 Jianyang Zeng 18
Affiliations

Affiliations

  • 1 Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, China.
  • 2 NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 Silexon AI Technology Co., Ltd., Nanjing, Jiangsu Province, China.
  • 5 Department of Computer Science, University of Illinois at Urbana-Champaign, Illinois, IL, USA.
  • 6 School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 7 School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
  • 8 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
  • 9 Department of Automation, Tsinghua University, Beijing, China.
  • 10 Inner Mongolia Alashan League Organization Establishment Committee Office Electronic Support Center, Alashan, Inner Mongolia, China.
  • 11 Convalife (Shanghai) Co., Ltd., Shanghai, China.
  • 12 Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 13 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
  • 14 Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, China. zhaodan2018@tsinghua.edu.cn.
  • 15 NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, China. jszfc@vip.sina.com.
  • 16 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu Province, China. jszfc@vip.sina.com.
  • 17 Convalife (Shanghai) Co., Ltd., Shanghai, China. steve.shen@convalife.com.
  • 18 Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, China. zengjy321@tsinghua.edu.cn.
  • # Contributed equally.
Abstract

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.

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