Signal Transduction and Targeted Therapy (Apr 2021)
An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
- Yiyue Ge,
- Tingzhong Tian,
- Suling Huang,
- Fangping Wan,
- Jingxin Li,
- Shuya Li,
- Xiaoting Wang,
- Hui Yang,
- Lixiang Hong,
- Nian Wu,
- Enming Yuan,
- Yunan Luo,
- Lili Cheng,
- Chengliang Hu,
- Yipin Lei,
- Hantao Shu,
- Xiaolong Feng,
- Ziyuan Jiang,
- Yunfu Wu,
- Ying Chi,
- Xiling Guo,
- Lunbiao Cui,
- Liang Xiao,
- Zeng Li,
- Chunhao Yang,
- Zehong Miao,
- Ligong Chen,
- Haitao Li,
- Hainian Zeng,
- Dan Zhao,
- Fengcai Zhu,
- Xiaokun Shen,
- Jianyang Zeng
Affiliations
- Yiyue Ge
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Tingzhong Tian
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Suling Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Fangping Wan
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Jingxin Li
- NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention
- Shuya Li
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Xiaoting Wang
- Silexon AI Technology Co., Ltd.
- Hui Yang
- Silexon AI Technology Co., Ltd.
- Lixiang Hong
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Nian Wu
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Enming Yuan
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Yunan Luo
- Department of Computer Science, University of Illinois at Urbana-Champaign
- Lili Cheng
- School of Pharmaceutical Sciences, Tsinghua University
- Chengliang Hu
- School of Pharmaceutical Sciences, Tsinghua University
- Yipin Lei
- Silexon AI Technology Co., Ltd.
- Hantao Shu
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Xiaolong Feng
- School of Electronic Information and Communications, Huazhong University of Science and Technology
- Ziyuan Jiang
- Department of Automation, Tsinghua University
- Yunfu Wu
- Inner Mongolia Alashan League Organization Establishment Committee Office Electronic Support Center
- Ying Chi
- NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention
- Xiling Guo
- NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention
- Lunbiao Cui
- NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention
- Liang Xiao
- Convalife (Shanghai) Co., Ltd.
- Zeng Li
- Convalife (Shanghai) Co., Ltd.
- Chunhao Yang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Zehong Miao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Ligong Chen
- School of Pharmaceutical Sciences, Tsinghua University
- Haitao Li
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University
- Hainian Zeng
- Silexon AI Technology Co., Ltd.
- Dan Zhao
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- Fengcai Zhu
- NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention
- Xiaokun Shen
- Convalife (Shanghai) Co., Ltd.
- Jianyang Zeng
- Institute for Interdisciplinary Information Sciences, Tsinghua University
- DOI
- https://doi.org/10.1038/s41392-021-00568-6
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 16
Abstract
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.
