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.
Highlights
IntroductionCOVID-19 has affected more than 176.887 million people in 194 countries and caused over 3.84 million deaths (as of 2021-06-18 https://www.cdc.gov.tw/) since its emergence at the end of 2019
COVID-19 has affected more than 176.887 million people in 194 countries and caused over 3.84 million deaths since its emergence at the end of 2019
Tocilizumab, a monoclonal antibody against IL-6 receptor (IL6-R) is an immunosuppressive drug originally developed for the treatment of rheumatoid arthritis (Scott, 2017) and systemic juvenile idiopathic arthritis (De Benedetti et al, 2012), but is currently under development as an alternative therapy for COVID-19 patients who are at risk of a cytokine storm (Rosas et al, 2021)
Summary
COVID-19 has affected more than 176.887 million people in 194 countries and caused over 3.84 million deaths (as of 2021-06-18 https://www.cdc.gov.tw/) since its emergence at the end of 2019. This disease is caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2), and disease progression is usually complexed with a cytokine storm and/or organ dysfunction (McElvaney et al, 2020). Tocilizumab, a monoclonal antibody against IL-6 receptor (IL6-R) is an immunosuppressive drug originally developed for the treatment of rheumatoid arthritis (Scott, 2017) and systemic juvenile idiopathic arthritis (De Benedetti et al, 2012), but is currently under development as an alternative therapy for COVID-19 patients who are at risk of a cytokine storm (Rosas et al, 2021). Mitigation of the cytokine storm that occurs in COVID19 patients is a sound therapeutic strategy
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