Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

Bafna, Khushboo; White, Kris M.; Harish, Balasubramanian; Rosales, Romel; Ramelot, Theresa; Acton, Thomas; Moreno, Elena; Kehrer, Thomas; Miorin, Lisa; Royer, Catherine A.; Garcı́a-Sastre, Adolfo; Krug, Robert M.; Montelione, Gaetano T.

doi:10.1016/j.celrep.2021.109133

Cited by 58 publications

(86 citation statements)

References 54 publications

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“…EC 50 s against SARS-CoV-2 were in the micromolar range, with the lowest EC 50 s (9 and 15 μM for simeprevir in A549-hACE2 and Vero E6 cells, respectively) approaching the EC 50 of remdesivir (0.1 and 2.5 μM in A549-hACE2 and Vero E6 cells, respectively); EC 50 s of remdesivir were in line with previously reported results ( 30 – 32 , 35 , 36 ). However, EC 50 s of PIs against SARS-CoV-2 were higher than the EC 50 s against HCV.…”

Section: Discussionsupporting

confidence: 91%

“…Inhibitor efficacy can be improved by combination treatments with synergistic and thus drug-saving effects as reported here for the combination of remdesivir with the macrocyclic PIs simeprevir, paritaprevir, or grazoprevir in Vero E6 cells and with simeprevir or grazoprevir in A549-hACE2 cells. Synergism was recently suggested for the combination of remdesivir with simeprevir ( 35 , 36 ) or grazoprevir ( 36 ) in short-term assays in Vero E6 cells ( 35 , 36 ) and human embryonic kidney (HEK293T) cells ( 36 ). Our extensive results in Vero E6 and A549-hACE2 cells using short-term drug interaction assays demonstrated that the mode of interaction between PI and remdesivir depended on the PI structure.…”

Section: Discussionmentioning

confidence: 99%

“…These studies were carried out in African green monkey kidney Vero E6 cells, and results were verified in human Huh7.5 hepatoma and A549 lung carcinoma cells, the latter engineered to constitutively express the human SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (hACE2). All culture systems were previously demonstrated to be relevant for studies of antivirals targeting SARS-CoV-2 ( 30 – 36 ). We further evaluated the efficacy of an HCV NS4A protease cofactor inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro

Gammeltoft

Zhou

Hernandez-Suarez

et al. 2021

Antimicrob Agents Chemother

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Antivirals targeting SARS-CoV-2 could improve treatment of COVID-19. We evaluated efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PI) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PI showed differential potency in short-term treatment assays based on detection of SARS-CoV-2 Spike protein in VeroE6 cells. Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PI. In short-term treatments, combination of macrocyclic but not linear PI with remdesivir showed synergism in VeroE6 and A549-hACE2 cells. Longer-term treatment of infected VeroE6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro

Gammeltoft

Zhou

Hernandez-Suarez

et al. 2021

Antimicrob Agents Chemother

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“…Multiple in vitro studies demonstrated that, at the nanomolar concentration, remdesivir is effective against SARS-CoV-2 infection [123][124][125]. Interestingly, a recent in vitro study revealed that a combination of remdesivir with repurposed hepatitis C virus (HCV) drugs was 10 times more effective at inhibiting SARS-CoV-2 [126]. In addition, in non-human primate studies, remdesivir treatment had a clinical benefit as reflected by reduced viral load and lung damage [127].…”

Section: Remdesivirmentioning

confidence: 99%

COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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“…Indeed, combination treatment with remdesivir plus baricitinib (a Janus kinase inhibitor) was superior to remdesivir alone in improving clinical status and recovery among COVID-19 patients (Kalil et al, 2021). A multi-center study reported that four approved drugs against hepatitis C that inhibit the papainlike protease of SARS-CoV-2 can enhance the antiviral effects of remdesivir by ten-fold in vitro (Bafna et al, 2021). Synergy between remdesivir and emetine has also been documented (Choy et al, 2020).…”

Section: A B D Cmentioning

confidence: 99%

Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

Tan

Chu

et al. 2021

Front. Cell. Infect. Microbiol.

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The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the Betacoronavirus genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an in vitro model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log10 and 1-log10, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) – above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log10 of live virus and 2.5-log10 of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.

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Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

Cited by 58 publications

References 54 publications

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 In Vitro

COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

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