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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [61872216, 81630103, 31900862, 31725014]; Jiangsu Provincial Emergency Project on Prevention and Control of COVID-19 Epidemic [BE2020601]; Nation Science and Technology Major Projects for Major New Drugs Innovation and Development [2018ZX09711003-004-002, 2019ZX09301010]; Pudong New Area Science and Technology Development Foundation [PKX2019-S08]; Turing AI Institute of Nanjing; Zhongguancun Haihua Institute for Frontier Information Technology
第一作者单位：[1]Tsinghua Univ, Inst Interdisciplinary Informat Sci, Beijing, Peoples R China[2]Jiangsu Prov Ctr Dis Control & Prevent, NHC Key Lab Enter Pathogen Microbiol, Nanjing, Jiangsu, Peoples R China
通讯作者：
通讯机构：[2]Jiangsu Prov Ctr Dis Control & Prevent, NHC Key Lab Enter Pathogen Microbiol, Nanjing, Jiangsu, Peoples R China[14]Nanjing Med Univ, Ctr Global Hlth, Nanjing, Jiangsu, Peoples R China
推荐引用方式(GB/T 7714)：
Ge Yiyue,Tian Tingzhong,Huang Suling,et al.An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19[J].SIGNAL TRANSDUCTION AND TARGETED THERAPY.2021,6(1):doi:10.1038/s41392-021-00568-6.
APA：
Ge, Yiyue,Tian, Tingzhong,Huang, Suling,Wan, Fangping,Li, Jingxin...&Zeng, Jianyang.(2021).An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19.SIGNAL TRANSDUCTION AND TARGETED THERAPY,6,(1)
MLA：
Ge, Yiyue,et al."An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19".SIGNAL TRANSDUCTION AND TARGETED THERAPY 6..1(2021)
医学