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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.
Shytaj, Iart Luca; Fares, Mohamed; Gallucci, Lara; Lucic, Bojana; Tolba, Mahmoud M; Zimmermann, Liv; Adler, Julia M; Xing, Na; Bushe, Judith; Gruber, Achim D; Ambiel, Ina; Taha Ayoub, Ahmed; Cortese, Mirko; Neufeldt, Christopher J; Stolp, Bettina; Sobhy, Mohamed Hossam; Fathy, Moustafa; Zhao, Min; Laketa, Vibor; Diaz, Ricardo Sobhie; Sutton, Richard E; Chlanda, Petr; Boulant, Steeve; Bartenschlager, Ralf; Stanifer, Megan L; Fackler, Oliver T; Trimpert, Jakob; Savarino, Andrea; Lusic, Marina.
  • Shytaj IL; Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, Germany.
  • Fares M; Federal University of São Paulo, Infectious Diseases Department, São Paulo, Brazil.
  • Gallucci L; Department of Hydrobiology, Veterinary Research Division, National Research Centre, Cairo, Egypt.
  • Lucic B; Center for Informatics Science (CIS), Nile University, Sheikh Zayed City, Giza, Egypt.
  • Tolba MM; Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, Germany.
  • Zimmermann L; Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, Germany.
  • Adler JM; German Center for Infection Research (DZIF), Heidelberg, Germany.
  • Xing N; Pharmaceutical Division, Ministry of Health and Population, Faiyum, Egypt.
  • Bushe J; Department of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, Germany.
  • Gruber AD; Schaller Research Groups, Center of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.
  • Ambiel I; Institut für Virologie, Freie Universität Berlingrid.14095.39, Berlin, Germany.
  • Taha Ayoub A; Institut für Virologie, Freie Universität Berlingrid.14095.39, Berlin, Germany.
  • Cortese M; Institute of Veterinary Pathology, Freie Universität Berlingrid.14095.39, Berlin, Germany.
  • Neufeldt CJ; Institute of Veterinary Pathology, Freie Universität Berlingrid.14095.39, Berlin, Germany.
  • Stolp B; Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, Germany.
  • Sobhy MH; Biomolecular Simulation Center, Department of Pharmaceutical Chemistry, Heliopolis University, Cairo, Egypt.
  • Fathy M; Department of Infectious Diseases, Molecular Virology, CIID, Heidelberg University, Heidelberg, Germany.
  • Zhao M; Department of Infectious Diseases, Molecular Virology, CIID, Heidelberg University, Heidelberg, Germany.
  • Laketa V; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • Diaz RS; Department of Infectious Diseases, Integrative Virology, Heidelberg University, Heidelberg, Germany.
  • Sutton RE; Biomolecular Simulation Center, Department of Pharmaceutical Chemistry, Heliopolis University, Cairo, Egypt.
  • Chlanda P; Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.
  • Boulant S; Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
  • Bartenschlager R; Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, New Haven, Connecticut, USA.
  • Stanifer ML; German Center for Infection Research (DZIF), Heidelberg, Germany.
  • Fackler OT; Department of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, Germany.
  • Trimpert J; Federal University of São Paulo, Infectious Diseases Department, São Paulo, Brazil.
  • Savarino A; Yale School of Medicine, Department of Internal Medicine, Section of Infectious Diseases, New Haven, Connecticut, USA.
  • Lusic M; Department of Infectious Diseases, Virology, CIID, Heidelberg University Hospital, Heidelberg, Germany.
mBio ; 13(2): e0370521, 2022 04 26.
Article in English | MEDLINE | ID: covidwho-1714363
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C, Chronic / COVID-19 Topics: Vaccines Limits: Animals / Humans Language: English Journal: MBio Year: 2022 Document Type: Article Affiliation country: Mbio.03705-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C, Chronic / COVID-19 Topics: Vaccines Limits: Animals / Humans Language: English Journal: MBio Year: 2022 Document Type: Article Affiliation country: Mbio.03705-21