A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

Ge, Y.; Tian, T.; Huang, S.; Wan, F.; Li, J.; Li, S.; Yang, H.; Hong, L.; Wu, N.; Yuan, E.; Cheng, L.; Lei, Y.; Shu, H.; Feng, X.; Jiang, Z.; Chi, Y.; Guo, X.; Cui, L.; Xiao, L.; Li, Z.; Yang, C.; Miao, Z.; Tang, H.; Chen, L.; Zeng, H.; Zhao, D.; Zhu, F.; Shen, X.; Zeng, J.

doi:10.1101/2020.03.11.986836

bioRxiv · 10.1101/2020.03.11.986836

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

Ge, Y.·Tian, T.·Huang, S.·Wan, F.·Li, J.·Li, S.·Yang, H.·Hong, L.·Wu, N.·Yuan, E.·Cheng, L.·Lei, Y.·Shu, H.·Feng, X.·Jiang, Z.·Chi, Y.·Guo, X.·Cui, L.·Xiao, L.·Li, Z.·Yang, C.·Miao, Z.·Tang, H.·Chen, L.·Zeng, H.·Zhao, D.·Zhu, F.·Shen, X.·Zeng, J.

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Abstract

The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both 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. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. 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 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.

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Ge, Y., Tian, T., Huang, S., Wan, F., Li, J., Li, S., Yang, H., Hong, L., Wu, N., Yuan, E., Cheng, L., Lei, Y., Shu, H., Feng, X., Jiang, Z., Chi, Y., Guo, X., Cui, L., Xiao, L., Li, Z., Yang, C., Miao, Z., Tang, H., Chen, L., Zeng, H., Zhao, D., Zhu, F., Shen, X., Zeng, J.. 2020-03-12. A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19. https://doi.org/10.1101/2020.03.11.986836

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