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

doi:10.1038/s41392-021-00568-6

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.

Authors

Yiyue Ge^#^{1

2}, Tingzhong Tian^#^{1

2}, Suling Huang^#³, Fangping Wan^#¹, Jingxin Li^#², Shuya Li¹, Xiaoting Wang⁴, Hui Yang⁴, Lixiang Hong¹, Nian Wu¹, Enming Yuan¹, Yunan Luo⁵, Lili Cheng⁶, Chengliang Hu⁶, Yipin Lei⁴, Hantao Shu¹, Xiaolong Feng^{7

8}, Ziyuan Jiang⁹, Yunfu Wu¹⁰, Ying Chi², Xiling Guo², Lunbiao Cui², Liang Xiao¹¹, Zeng Li¹¹, Chunhao Yang³, Zehong Miao³, Ligong Chen^{6

12}, Haitao Li¹³, Hainian Zeng⁴, Dan Zhao¹⁴, Fengcai Zhu^{15

16}, Xiaokun Shen¹⁷, Jianyang Zeng¹⁸

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. [email protected].
¹⁵ NHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and Prevention, Nanjing, Jiangsu Province, China. [email protected].
¹⁶ Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu Province, China. [email protected].
¹⁷ Convalife (Shanghai) Co., Ltd., Shanghai, China. [email protected].
¹⁸ Institute for Interdisciplinary Information Sciences, Tsinghua University, Beijing, China. [email protected].

^# 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / therapeutic use*
COVID-19 / metabolism*
COVID-19 Drug Treatment*
Computer Simulation*
Drug Repositioning*
Humans
Models, Biological*
SARS-CoV-2 / metabolism*

Substances

Antiviral Agents