Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

Hsing Yu Hsu; Cheng Wei Yang; Yue Zhi Lee; Yi Ling Lin; Sui Yuan Chang; Ruey Bing Yang; Jian Jong Liang; Tai Ling Chao; Chun Che Liao; Han Chieh Kao; Szu Huei Wu; Jang Yang Chang; Huey Kang Sytwu; Chiung Tong Chen; Shiow Ju Lee

doi:10.3389/fphar.2021.706901

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

Hsing Yu Hsu, Cheng Wei Yang, Yue Zhi Lee, Yi Ling Lin, Sui Yuan Chang, Ruey Bing Yang, Jian Jong Liang, Tai Ling Chao, Chun Che Liao, Han Chieh Kao, Szu Huei Wu, Jang Yang Chang, Huey Kang Sytwu, Chiung Tong Chen, Shiow Ju Lee

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Remdesivir, a prodrug targeting RNA-dependent-RNA-polymerase, and cyclosporine, a calcineurin inhibitor, individually exerted inhibitory activity against human coronavirus OC43 (HCoV-OC43) in HCT-8 and MRC-5 cells at EC₅₀ values of 96 ± 34 ∼ 85 ± 23 nM and 2,920 ± 364 ∼ 4,419 ± 490 nM, respectively. When combined, these two drugs synergistically inhibited HCoV-OC43 in both HCT-8 and MRC-5 cells assayed by immunofluorescence assay (IFA). Remdesivir and cyclosporine also separately reduced IL-6 production induced by HCoV-OC43 in human lung fibroblasts MRC-5 cells with EC₅₀ values of 224 ± 53 nM and 1,292 ± 352 nM, respectively; and synergistically reduced it when combined. Similar trends were observed for SARS-CoV-2, which were 1) separately inhibited by remdesivir and cyclosporine with respective EC₅₀ values of 3,962 ± 303 nM and 7,213 ± 143 nM by IFA, and 291 ± 91 nM and 6,767 ± 1,827 nM by a plaque-formation assay; and 2) synergistically inhibited by their combination, again by IFA and plaque-formation assay. Collectively, these results suggest that the combination of remdesivir and cyclosporine merits further study as a possible treatment for COVID-19 complexed with a cytokine storm.

Original language	English
Article number	706901
Journal	Frontiers in Pharmacology
Volume	12
DOIs	https://doi.org/10.3389/fphar.2021.706901
Publication status	Published - Aug 13 2021
Externally published	Yes

Keywords

COVID-19
cyclosporine
IL-6
IL-8
OC43
remdesivir
SARS-CoV-2
synergistic

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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10.3389/fphar.2021.706901

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Hsu, H. Y., Yang, C. W., Lee, Y. Z., Lin, Y. L., Chang, S. Y., Yang, R. B., Liang, J. J., Chao, T. L., Liao, C. C., Kao, H. C., Wu, S. H., Chang, J. Y., Sytwu, H. K., Chen, C. T., & Lee, S. J. (2021). Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2. Frontiers in Pharmacology, 12, Article 706901. https://doi.org/10.3389/fphar.2021.706901

@article{9d237fee73bf4300bc04d9dd30aaae5c,

title = "Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2",

abstract = "Remdesivir, a prodrug targeting RNA-dependent-RNA-polymerase, and cyclosporine, a calcineurin inhibitor, individually exerted inhibitory activity against human coronavirus OC43 (HCoV-OC43) in HCT-8 and MRC-5 cells at EC50 values of 96 ± 34 ∼ 85 ± 23 nM and 2,920 ± 364 ∼ 4,419 ± 490 nM, respectively. When combined, these two drugs synergistically inhibited HCoV-OC43 in both HCT-8 and MRC-5 cells assayed by immunofluorescence assay (IFA). Remdesivir and cyclosporine also separately reduced IL-6 production induced by HCoV-OC43 in human lung fibroblasts MRC-5 cells with EC50 values of 224 ± 53 nM and 1,292 ± 352 nM, respectively; and synergistically reduced it when combined. Similar trends were observed for SARS-CoV-2, which were 1) separately inhibited by remdesivir and cyclosporine with respective EC50 values of 3,962 ± 303 nM and 7,213 ± 143 nM by IFA, and 291 ± 91 nM and 6,767 ± 1,827 nM by a plaque-formation assay; and 2) synergistically inhibited by their combination, again by IFA and plaque-formation assay. Collectively, these results suggest that the combination of remdesivir and cyclosporine merits further study as a possible treatment for COVID-19 complexed with a cytokine storm.",

keywords = "COVID-19, cyclosporine, IL-6, IL-8, OC43, remdesivir, SARS-CoV-2, synergistic",

author = "Hsu, {Hsing Yu} and Yang, {Cheng Wei} and Lee, {Yue Zhi} and Lin, {Yi Ling} and Chang, {Sui Yuan} and Yang, {Ruey Bing} and Liang, {Jian Jong} and Chao, {Tai Ling} and Liao, {Chun Che} and Kao, {Han Chieh} and Wu, {Szu Huei} and Chang, {Jang Yang} and Sytwu, {Huey Kang} and Chen, {Chiung Tong} and Lee, {Shiow Ju}",

note = "Funding Information: The authors gratefully acknowledge Kung-Yee Liang, National Health Research Institutes, for his full support on this work. We also would like to acknowledge Taiwan CDC for providing SARS-CoV-2 TCDC#4 (hCoV-19/Taiwan/4/2020) and the services provided by the Biosafety Level-3 Laboratory of the First Core Laboratory, National Taiwan University College of Medicine and by IBMS P3 facility at Academia Sinica. Funding Information: This work was funded by the National Health Research Institutes, Taiwan, R.O.C.; Academia Sinica (AS-CFII-108-102); the Ministry of Science and Technology, Taiwan, R.O.C (MOST 109-2327-B-400-003; MOST 109-3114-Y-001-001; MOST 109-2811-B-400-518; MOST109-2327-B-002–009); and the Ministry of Health and Welfare, Taiwan, R.O.C. for an emergent grant of COVID-19. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Hsu, Yang, Lee, Lin, Chang, Yang, Liang, Chao, Liao, Kao, Wu, Chang, Sytwu, Chen and Lee.",

year = "2021",

month = aug,

day = "13",

doi = "10.3389/fphar.2021.706901",

language = "English",

volume = "12",

journal = "Frontiers in Pharmacology",

issn = "1663-9812",

publisher = "Frontiers Media SA",

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T1 - Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

AU - Hsu, Hsing Yu

AU - Yang, Cheng Wei

AU - Lee, Yue Zhi

AU - Lin, Yi Ling

AU - Chang, Sui Yuan

AU - Yang, Ruey Bing

AU - Liang, Jian Jong

AU - Chao, Tai Ling

AU - Liao, Chun Che

AU - Kao, Han Chieh

AU - Wu, Szu Huei

AU - Chang, Jang Yang

AU - Sytwu, Huey Kang

AU - Chen, Chiung Tong

AU - Lee, Shiow Ju

N1 - Funding Information: The authors gratefully acknowledge Kung-Yee Liang, National Health Research Institutes, for his full support on this work. We also would like to acknowledge Taiwan CDC for providing SARS-CoV-2 TCDC#4 (hCoV-19/Taiwan/4/2020) and the services provided by the Biosafety Level-3 Laboratory of the First Core Laboratory, National Taiwan University College of Medicine and by IBMS P3 facility at Academia Sinica. Funding Information: This work was funded by the National Health Research Institutes, Taiwan, R.O.C.; Academia Sinica (AS-CFII-108-102); the Ministry of Science and Technology, Taiwan, R.O.C (MOST 109-2327-B-400-003; MOST 109-3114-Y-001-001; MOST 109-2811-B-400-518; MOST109-2327-B-002–009); and the Ministry of Health and Welfare, Taiwan, R.O.C. for an emergent grant of COVID-19. Publisher Copyright: © Copyright © 2021 Hsu, Yang, Lee, Lin, Chang, Yang, Liang, Chao, Liao, Kao, Wu, Chang, Sytwu, Chen and Lee.

PY - 2021/8/13

Y1 - 2021/8/13

N2 - Remdesivir, a prodrug targeting RNA-dependent-RNA-polymerase, and cyclosporine, a calcineurin inhibitor, individually exerted inhibitory activity against human coronavirus OC43 (HCoV-OC43) in HCT-8 and MRC-5 cells at EC50 values of 96 ± 34 ∼ 85 ± 23 nM and 2,920 ± 364 ∼ 4,419 ± 490 nM, respectively. When combined, these two drugs synergistically inhibited HCoV-OC43 in both HCT-8 and MRC-5 cells assayed by immunofluorescence assay (IFA). Remdesivir and cyclosporine also separately reduced IL-6 production induced by HCoV-OC43 in human lung fibroblasts MRC-5 cells with EC50 values of 224 ± 53 nM and 1,292 ± 352 nM, respectively; and synergistically reduced it when combined. Similar trends were observed for SARS-CoV-2, which were 1) separately inhibited by remdesivir and cyclosporine with respective EC50 values of 3,962 ± 303 nM and 7,213 ± 143 nM by IFA, and 291 ± 91 nM and 6,767 ± 1,827 nM by a plaque-formation assay; and 2) synergistically inhibited by their combination, again by IFA and plaque-formation assay. Collectively, these results suggest that the combination of remdesivir and cyclosporine merits further study as a possible treatment for COVID-19 complexed with a cytokine storm.

AB - Remdesivir, a prodrug targeting RNA-dependent-RNA-polymerase, and cyclosporine, a calcineurin inhibitor, individually exerted inhibitory activity against human coronavirus OC43 (HCoV-OC43) in HCT-8 and MRC-5 cells at EC50 values of 96 ± 34 ∼ 85 ± 23 nM and 2,920 ± 364 ∼ 4,419 ± 490 nM, respectively. When combined, these two drugs synergistically inhibited HCoV-OC43 in both HCT-8 and MRC-5 cells assayed by immunofluorescence assay (IFA). Remdesivir and cyclosporine also separately reduced IL-6 production induced by HCoV-OC43 in human lung fibroblasts MRC-5 cells with EC50 values of 224 ± 53 nM and 1,292 ± 352 nM, respectively; and synergistically reduced it when combined. Similar trends were observed for SARS-CoV-2, which were 1) separately inhibited by remdesivir and cyclosporine with respective EC50 values of 3,962 ± 303 nM and 7,213 ± 143 nM by IFA, and 291 ± 91 nM and 6,767 ± 1,827 nM by a plaque-formation assay; and 2) synergistically inhibited by their combination, again by IFA and plaque-formation assay. Collectively, these results suggest that the combination of remdesivir and cyclosporine merits further study as a possible treatment for COVID-19 complexed with a cytokine storm.

KW - COVID-19

KW - cyclosporine

KW - IL-6

KW - IL-8

KW - OC43

KW - remdesivir

KW - SARS-CoV-2

KW - synergistic

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U2 - 10.3389/fphar.2021.706901

DO - 10.3389/fphar.2021.706901

M3 - Article

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VL - 12

JO - Frontiers in Pharmacology

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ER -

Remdesivir and Cyclosporine Synergistically Inhibit the Human Coronaviruses OC43 and SARS-CoV-2

Abstract

Keywords

ASJC Scopus subject areas

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