An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19
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 advan...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-04-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-021-00568-6 |
| _version_ | 1818727127968645120 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yiyue Ge |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T22:09:10Z |
| format | Article |
| id | doaj.art-4f3f4d21df9d4b8b88ef95b4b0a08a89 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-12-17T22:09:10Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-4f3f4d21df9d4b8b88ef95b4b0a08a892022-12-21T21:30:47ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352021-04-016111610.1038/s41392-021-00568-6An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19Yiyue Ge0Tingzhong Tian1Suling Huang2Fangping Wan3Jingxin Li4Shuya Li5Xiaoting Wang6Hui Yang7Lixiang Hong8Nian Wu9Enming Yuan10Yunan Luo11Lili Cheng12Chengliang Hu13Yipin Lei14Hantao Shu15Xiaolong Feng16Ziyuan Jiang17Yunfu Wu18Ying Chi19Xiling Guo20Lunbiao Cui21Liang Xiao22Zeng Li23Chunhao Yang24Zehong Miao25Ligong Chen26Haitao Li27Hainian Zeng28Dan Zhao29Fengcai Zhu30Xiaokun Shen31Jianyang Zeng32Institute for Interdisciplinary Information Sciences, Tsinghua UniversityInstitute for Interdisciplinary Information Sciences, Tsinghua UniversityShanghai Institute of Materia Medica, Chinese Academy of SciencesInstitute for Interdisciplinary Information Sciences, Tsinghua UniversityNHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and PreventionInstitute for Interdisciplinary Information Sciences, Tsinghua UniversitySilexon AI Technology Co., Ltd.Silexon AI Technology Co., Ltd.Institute for Interdisciplinary Information Sciences, Tsinghua UniversityInstitute for Interdisciplinary Information Sciences, Tsinghua UniversityInstitute for Interdisciplinary Information Sciences, Tsinghua UniversityDepartment of Computer Science, University of Illinois at Urbana-ChampaignSchool of Pharmaceutical Sciences, Tsinghua UniversitySchool of Pharmaceutical Sciences, Tsinghua UniversitySilexon AI Technology Co., Ltd.Institute for Interdisciplinary Information Sciences, Tsinghua UniversitySchool of Electronic Information and Communications, Huazhong University of Science and TechnologyDepartment of Automation, Tsinghua UniversityInner Mongolia Alashan League Organization Establishment Committee Office Electronic Support CenterNHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and PreventionNHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and PreventionNHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and PreventionConvalife (Shanghai) Co., Ltd.Convalife (Shanghai) Co., Ltd.Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Materia Medica, Chinese Academy of SciencesSchool of Pharmaceutical Sciences, Tsinghua UniversityBeijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua UniversitySilexon AI Technology Co., Ltd.Institute for Interdisciplinary Information Sciences, Tsinghua UniversityNHC Key laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Diseases Control and PreventionConvalife (Shanghai) Co., Ltd.Institute for Interdisciplinary Information Sciences, Tsinghua UniversityAbstract 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.https://doi.org/10.1038/s41392-021-00568-6 |
| spellingShingle | 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 An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 Signal Transduction and Targeted Therapy |
| title | An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 |
| title_full | An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 |
| title_fullStr | An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 |
| title_full_unstemmed | An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 |
| title_short | An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 |
| title_sort | integrative drug repositioning framework discovered a potential therapeutic agent targeting covid 19 |
| url | https://doi.org/10.1038/s41392-021-00568-6 |
| work_keys_str_mv | AT yiyuege anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT tingzhongtian anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT sulinghuang anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT fangpingwan anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT jingxinli anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT shuyali anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaotingwang anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT huiyang anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lixianghong anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT nianwu anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT enmingyuan anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yunanluo anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lilicheng anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT chenglianghu anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yipinlei anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT hantaoshu anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaolongfeng anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT ziyuanjiang anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yunfuwu anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yingchi anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xilingguo anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lunbiaocui anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT liangxiao anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT zengli anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT chunhaoyang anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT zehongmiao anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT ligongchen anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT haitaoli anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT hainianzeng anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT danzhao anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT fengcaizhu anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaokunshen anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT jianyangzeng anintegrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yiyuege integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT tingzhongtian integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT sulinghuang integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT fangpingwan integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT jingxinli integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT shuyali integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaotingwang integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT huiyang integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lixianghong integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT nianwu integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT enmingyuan integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yunanluo integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lilicheng integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT chenglianghu integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yipinlei integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT hantaoshu integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaolongfeng integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT ziyuanjiang integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yunfuwu integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT yingchi integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xilingguo integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT lunbiaocui integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT liangxiao integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT zengli integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT chunhaoyang integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT zehongmiao integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT ligongchen integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT haitaoli integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT hainianzeng integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT danzhao integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT fengcaizhu integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT xiaokunshen integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 AT jianyangzeng integrativedrugrepositioningframeworkdiscoveredapotentialtherapeuticagenttargetingcovid19 |