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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 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.

SUBMITTER: Ge Y

PROVIDER: S-EPMC8065335 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19.

Ge Yiyue Y Tian Tingzhong T Huang Suling S Wan Fangping F Li Jingxin J Li Shuya S Wang Xiaoting X Yang Hui H Hong Lixiang L Wu Nian N Yuan Enming E Luo Yunan Y Cheng Lili L Hu Chengliang C Lei Yipin Y Shu Hantao H Feng Xiaolong X Jiang Ziyuan Z Wu Yunfu Y Chi Ying Y Guo Xiling X Cui Lunbiao L Xiao Liang L Li Zeng Z Yang Chunhao C Miao Zehong Z Chen Ligong L Li Haitao H Zeng Hainian H Zhao Dan D Zhu Fengcai F Shen Xiaokun X Zeng Jianyang J

Signal transduction and targeted therapy 20210424 1

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 agains ...[more]

PMID: 33895786

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Project description:Background: YAP, coded by YAP1 gene, is critical in the Hippo pathway. It has been reported to be involved in the tumorigenesis and progression of several cancers. However, its roles on tumor cell proliferation in diverse cancers remain to be elucidated. And there is currently no clinically feasible drug that can directly target YAP in cancers. This research aimed to explore the regulatory mechanism of YAP in promoting tumor proliferation of multiple cancers, in order to find new strategies for inhibiting the overgrowth of YAP-driven cancers. Methods: We investigated the expression pattern of YAP1 in pan-cancer across numerous databases and our cohorts. First, univariate Cox regression analysis and survival analysis were used to evaluate the effect of YAP1 on the prognosis of cancer patients. Second, TIMER was used to explore the relationship between YAP1 expression and tumor cell proliferation. Third, functional and pathway enrichment was performed to search for targets of YAP involved in cell cycle in cancers. At last, GDSC and CCLE datasets were used to assess the correlation between SKP2 expression and MLN4924 IC50 values. Results: Differential expression analysis of multiple databases and qPCR validation showed that YAP1 was generally overexpressed in pan-cancers. Survival analysis revealed that YAP1 over-expression was significantly related to poor prognosis of patients with PAAD. The expression level of YAP1 was positively correlated with the proliferation in varieties of tumors. Further, SKP2 was confirmed as a target of YAP in promoting tumor cell proliferation. In addition, SKP2 expression was negatively correlated with MLN4924 IC50 values in almost all cancer types. Conclusion: YAP1 is frequently overexpressed in human cancers. YAP promoted tumor cell proliferation by up-regulating SKP2 expression in multiple cancers. The comprehensive pan-cancer analysis suggested that inhibition of Skp2 with MLN4924 might be an effective therapeutic strategy for attenuating tumor cell proliferation in YAP-driven cancers.

Dataset Information

An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19.

Publications

An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19.

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