The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters
ABSTRACT Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of dru...
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American Society for Microbiology
2022-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03705-21 |
| _version_ | 1828467947413176320 |
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| author | Iart Luca Shytaj Mohamed Fares Lara Gallucci Bojana Lucic Mahmoud M. Tolba Liv Zimmermann Julia M. Adler Na Xing Judith Bushe Achim D. Gruber Ina Ambiel Ahmed Taha Ayoub Mirko Cortese Christopher J. Neufeldt Bettina Stolp Mohamed Hossam Sobhy Moustafa Fathy Min Zhao Vibor Laketa Ricardo Sobhie Diaz Richard E. Sutton Petr Chlanda Steeve Boulant Ralf Bartenschlager Megan L. Stanifer Oliver T. Fackler Jakob Trimpert Andrea Savarino Marina Lusic |
| author_facet | Iart Luca Shytaj Mohamed Fares Lara Gallucci Bojana Lucic Mahmoud M. Tolba Liv Zimmermann Julia M. Adler Na Xing Judith Bushe Achim D. Gruber Ina Ambiel Ahmed Taha Ayoub Mirko Cortese Christopher J. Neufeldt Bettina Stolp Mohamed Hossam Sobhy Moustafa Fathy Min Zhao Vibor Laketa Ricardo Sobhie Diaz Richard E. Sutton Petr Chlanda Steeve Boulant Ralf Bartenschlager Megan L. Stanifer Oliver T. Fackler Jakob Trimpert Andrea Savarino Marina Lusic |
| author_sort | Iart Luca Shytaj |
| collection | DOAJ |
| description | ABSTRACT Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy. |
| first_indexed | 2024-12-11T04:14:25Z |
| format | Article |
| id | doaj.art-30bf4bc23be645f7a9bdfa7dd16e08e5 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-11T04:14:25Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-30bf4bc23be645f7a9bdfa7dd16e08e52022-12-22T01:21:17ZengAmerican Society for MicrobiologymBio2150-75112022-04-0113210.1128/mbio.03705-21The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian HamstersIart Luca Shytaj0Mohamed Fares1Lara Gallucci2Bojana Lucic3Mahmoud M. Tolba4Liv Zimmermann5Julia M. Adler6Na Xing7Judith Bushe8Achim D. Gruber9Ina Ambiel10Ahmed Taha Ayoub11Mirko Cortese12Christopher J. Neufeldt13Bettina Stolp14Mohamed Hossam Sobhy15Moustafa Fathy16Min Zhao17Vibor Laketa18Ricardo Sobhie Diaz19Richard E. Sutton20Petr Chlanda21Steeve Boulant22Ralf Bartenschlager23Megan L. Stanifer24Oliver T. Fackler25Jakob Trimpert26Andrea Savarino27Marina Lusic28Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyDepartment of Hydrobiology, Veterinary Research Division, National Research Centre, Cairo, EgyptDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyPharmaceutical Division, Ministry of Health and Population, Faiyum, EgyptDepartment of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, GermanyInstitut für Virologie, Freie Universität Berlin, Berlin, GermanyInstitut für Virologie, Freie Universität Berlin, Berlin, GermanyInstitute of Veterinary Pathology, Freie Universität Berlin, Berlin, GermanyInstitute of Veterinary Pathology, Freie Universität Berlin, Berlin, GermanyDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyBiomolecular Simulation Center, Department of Pharmaceutical Chemistry, Heliopolis University, Cairo, EgyptDepartment of Infectious Diseases, Molecular Virology, CIID, Heidelberg University, Heidelberg, GermanyDepartment of Infectious Diseases, Molecular Virology, CIID, Heidelberg University, Heidelberg, GermanyDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyBiomolecular Simulation Center, Department of Pharmaceutical Chemistry, Heliopolis University, Cairo, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Minia University, Minia, EgyptYale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, New Haven, Connecticut, USAGerman Center for Infection Research (DZIF), Heidelberg, GermanyFederal University of São Paulo, Infectious Diseases Department, São Paulo, BrazilYale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, New Haven, Connecticut, USADepartment of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, GermanyDepartment of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, GermanyGerman Center for Infection Research (DZIF), Heidelberg, GermanyDepartment of Infectious Diseases, Molecular Virology, CIID, Heidelberg University, Heidelberg, GermanyDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyInstitut für Virologie, Freie Universität Berlin, Berlin, GermanyDepartment of Infectious Diseases, Italian Institute of Health, Rome, ItalyDepartment of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, GermanyABSTRACT Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.https://journals.asm.org/doi/10.1128/mbio.03705-21COVID-19SARS-CoV-2spike proteindirect-acting antiviralscobicistatremdesivir |
| spellingShingle | Iart Luca Shytaj Mohamed Fares Lara Gallucci Bojana Lucic Mahmoud M. Tolba Liv Zimmermann Julia M. Adler Na Xing Judith Bushe Achim D. Gruber Ina Ambiel Ahmed Taha Ayoub Mirko Cortese Christopher J. Neufeldt Bettina Stolp Mohamed Hossam Sobhy Moustafa Fathy Min Zhao Vibor Laketa Ricardo Sobhie Diaz Richard E. Sutton Petr Chlanda Steeve Boulant Ralf Bartenschlager Megan L. Stanifer Oliver T. Fackler Jakob Trimpert Andrea Savarino Marina Lusic The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters mBio COVID-19 SARS-CoV-2 spike protein direct-acting antivirals cobicistat remdesivir |
| title | The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters |
| title_full | The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters |
| title_fullStr | The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters |
| title_full_unstemmed | The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters |
| title_short | The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters |
| title_sort | fda approved drug cobicistat synergizes with remdesivir to inhibit sars cov 2 replication in vitro and decreases viral titers and disease progression in syrian hamsters |
| topic | COVID-19 SARS-CoV-2 spike protein direct-acting antivirals cobicistat remdesivir |
| url | https://journals.asm.org/doi/10.1128/mbio.03705-21 |
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