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

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

doi:10.3389/fphar.2021.706901

Cited by 17 publications

(17 citation statements)

References 40 publications

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“…Previously, we screened drugs covered by Taiwan Health Insurance for anti-viral activity in HCoV-OC43-infected HCT-8 cells to identify those potentially suitable for repurposing as an anti-SARS-CoV-2 agent to combat COVID-19 [ 5 ]. In this continued work, we found that ciclesonide, an inhaled corticosteroid used to treat hay fever, asthma, and allergic rhinitis, increased IκBα protein levels and decreased p-p65 protein levels ( Figure 2 B) over 30 h after the infection of MRC-5 cells with HCoV-OC43.…”

Section: Resultsmentioning

confidence: 99%

“…For the anti-coronaviral activity studies, an immunofluorescent assay was performed as described [ 5 ]. Anti-HCoV-OC43 N protein (Merck Millipore, Mab9013) and FITC-conjugated anti-mouse immunoglobulin (MP Biomedicals, Irvine, CA, USA, 55499) were used as the primary and second antibodies for anti-HCoV-OC43.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to amplifying itself in an infected host, SARS-CoV-2 also induces cytokine production, often resulting in a cytokine storm whose mitigation is a potential COVID-19 treatment strategy, especially in critically ill patients [ 3 ]. Intervention strategies targeting the cytokine storm include traditional anti-inflammatories and immunosuppressives, e.g., corticosteroids such as dexamethasone and cyclosporine, as well as newly developed biologics, e.g., monoclonal antibodies targeting pro-inflammatory cytokines, and recombinant cytokines [ 4 , 5 ]. The current standard of care for hospitalized COVID-19 patients includes strategies to combat the cytokine storm such as dexamethasone and methylprednisolone [ 6 , 7 , 8 , 9 , 10 ], as well as those to address the replication of the virus itself [ 11 , 12 ], such as remdesivir.…”

Section: Introductionmentioning

confidence: 99%

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The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b

et al. 2022

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Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, and MCP-1 by increasing IκBα protein levels and significantly decreasing p65 nuclear translocation. Furthermore, we found that the combination of ciclesonide and dbq33b, a potent tylophorine-based coronavirus inhibitor that affects coronavirus-induced NF-κB activation a little, additively and synergistically decreased coronavirus-induced IL-6, IL-8, and MCP-1 cytokine levels, and synergistically inhibited the replication of both HCoV-OC43 and SARS-CoV-2. Collectively, the combination of ciclesonide and dbq33b merits consideration as a treatment for COVID-19 patients who may otherwise be overwhelmed by high viral loads and an NF-κB-mediated cytokine storm.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b

et al. 2022

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“…Of note, TAC concentrations that are required to inhibit SARS-CoV-2 replication likely correlate with intolerable or toxic concentrations in humans (EC 50 of 0.2 µM equals 160 ng/ml for TAC), without even taking into account that the free fraction in traffic is only ~10%. For CsA and VCS 0.2 µM correspond to a concentration of 241 and 243 ng/ml respectively (40,69), which may come closer to peak concentrations in vivo. Moreover, the distribution of VCS over different organs might also be beneficial as concentrations in the lungs are higher than in blood (40,45).…”

Section: Discussionmentioning

confidence: 92%

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture

et al. 2022

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Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI’s in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

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“…were subjected to IFA 24 h.p.i. as described or harvested for western analyses using an antibody (MAB9013) against OC43 N protein [8,34].…”

Section: Cells Viruses Immunofluorescence Assay (Ifa) and Cytotoxicit...mentioning

confidence: 99%

Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch

et al. 2022

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JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC50 values of 5.2 ± 0.3 μM against transmissible gastroenteritis coronavirus (TGEV) and 4.3 ± 0.3 μM against human flu coronavirus OC43. However, although the IR and IGF-1R signaling pathways are activated by insulin or IGF-1 in swine testis cells, they are not triggered upon TGEV infection. AG1024, therefore, inhibits coronaviral replication and downregulates JAK1 protein levels independently of IR and IGF-1R. Moreover, JAK1 proteolysis caused by AG1024 was found through activation of upstream Ndfip1/2 and its effector NEDD4-like E3 ligase Itch. In addition, ouabain, which was reported to mediate JAK1 proteolysis causing anti-coronaviral activity by activation of Ndfip1/2 and NEDD4 E3 ligase, additively inhibited anti-coronaviral activity and JAK1 diminishment in combination with AG1024. This study provides novel insights into the pharmacological effects of AG1024 and Itch E3 ligase mediated JAK1 proteolysis and identified Ndfip1/2 as a cognate effector for JAK1 proteolysis via the diversified E3 ligases NEDD4 and NEDD4-like Itch. These findings are expected to provide valued information for the future development of anti-viral agents.

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

Cited by 17 publications

References 40 publications

The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b

The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture

Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch

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