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Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro

Tesia Bobrowski, Lu Chen, Richard T. Eastman, Zina Itkin, Paul Shinn, Catherine Chen, Hui Guo, Wei Zheng, Sam Michael, Anton Simeonov, View ORCID ProfileMatthew D. Hall, Alexey V. Zakharov, Eugene N. Muratov
doi: https://doi.org/10.1101/2020.06.29.178889
Tesia Bobrowski
aLaboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA
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Lu Chen
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Richard T. Eastman
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Zina Itkin
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Paul Shinn
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Catherine Chen
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Hui Guo
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Wei Zheng
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Sam Michael
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Anton Simeonov
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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Matthew D. Hall
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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  • ORCID record for Matthew D. Hall
Alexey V. Zakharov
bNational Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States
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  • For correspondence: murik@email.unc.edu alexey.zakharov@nih.gov
Eugene N. Muratov
aLaboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA
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  • For correspondence: murik@email.unc.edu alexey.zakharov@nih.gov
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Abstract

COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://opendata.ncats.nih.gov/covid19/matrix

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro
Tesia Bobrowski, Lu Chen, Richard T. Eastman, Zina Itkin, Paul Shinn, Catherine Chen, Hui Guo, Wei Zheng, Sam Michael, Anton Simeonov, Matthew D. Hall, Alexey V. Zakharov, Eugene N. Muratov
bioRxiv 2020.06.29.178889; doi: https://doi.org/10.1101/2020.06.29.178889
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Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro
Tesia Bobrowski, Lu Chen, Richard T. Eastman, Zina Itkin, Paul Shinn, Catherine Chen, Hui Guo, Wei Zheng, Sam Michael, Anton Simeonov, Matthew D. Hall, Alexey V. Zakharov, Eugene N. Muratov
bioRxiv 2020.06.29.178889; doi: https://doi.org/10.1101/2020.06.29.178889

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