An Integrative Drug Repositioning Framework Discovered a Potential Therapeutic Agent Targeting COVID-19
Yiyue Ge#, Tingzhong Tian#, Sulin 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*
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.