Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.

التفاصيل البيبلوغرافية
العنوان:	Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.
المؤلفون:	García-Crespo C; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain., de Ávila AI; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain., Gallego I; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain., Soria ME; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain., Durán-Pastor A; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain., Somovilla P; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain.; Departamento de Biología Molecular, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain., Martínez-González B; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain., Muñoz-Flores J; GMS Management Solutions S.L., Torre Picasso, Madrid, Spain., Mínguez P; Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.; Bioinformatics Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain., Salar-Vidal L; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Centre for Biomedical Network Research on Infectious Diseases (CIBERINFEC), Madrid, Spain., Esteban-Muñoz M; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain., Cañar-Camacho E; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain., Ferrer-Orta C; Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas (IBMB-CSIC), Barcelona, Spain., Zuñiga S; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain., Sola I; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain., Enjuanes L; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain., Esteban J; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Centre for Biomedical Network Research on Infectious Diseases (CIBERINFEC), Madrid, Spain., Fernández-Roblas R; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Centre for Biomedical Network Research on Infectious Diseases (CIBERINFEC), Madrid, Spain., Gadea I; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Centre for Biomedical Network Research on Infectious Diseases (CIBERINFEC), Madrid, Spain., Gómez J; Instituto de Parasitología y Biomedicina 'López-Neyra' (CSIC), Parque Tecnológico Ciencias de la Salud, Armilla, Granada, Spain., Verdaguer N; Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas (IBMB-CSIC), Barcelona, Spain., Domingo E; Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Campus de Cantoblanco, Madrid, Spain., Perales C; Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.; Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
المصدر:	British journal of pharmacology [Br J Pharmacol] 2024 Aug; Vol. 181 (15), pp. 2636-2654. Date of Electronic Publication: 2024 Apr 14.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
أسماء مطبوعة:	Publication: London : Wiley Original Publication: London, Macmillian Journals Ltd.
مواضيع طبية MeSH:	Alanine/analogs & derivatives , Alanine/pharmacology , Ribavirin/pharmacology , Antiviral Agents/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Drug Synergism* , SARS-CoV-2*/drug effects, Chlorocebus aethiops ; Vero Cells ; Animals ; Humans ; COVID-19 Drug Treatment ; COVID-19/virology
مستخلص:	Background and Purpose: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. Experimental Approach: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured. Key Results: Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species. Conclusion and Implications: SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression. (© 2024 British Pharmacological Society.)
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معلومات مُعتمدة:	13-2022-008566 Consejería de Educación e Investigación; S2018/BAA-4370 Consejería de Educación e Investigación; 202220I116 Ministerio de Ciencia e Innovación; PID2020-113888RB-I00 Ministerio de Ciencia e Innovación; PID2020-117976GB-I00 Ministerio de Ciencia e Innovación; CSIC-COV19-014 Consejo Superior de Investigaciones Científicas; CA1/RSUE/2021 Ministerio de Ciencia, Innovación y Universidades; PRE2018-083422 Ministerio de Ciencia, Innovación y Universidades; CPII21/00015 Instituto de Salud Carlos III; PFIS FI19/00119 Instituto de Salud Carlos III; PI21/00139 Instituto de Salud Carlos III; 202136-30 Fundació La Marató de TV3; 202136-31 Fundació La Marató de TV3
فهرسة مساهمة:	Keywords: COVID‐19 therapy; Quasi‐species; error catastrophe; lethal mutagenesis; virus diversity
المشرفين على المادة:	OF5P57N2ZX (Alanine) 3QKI37EEHE (remdesivir) 49717AWG6K (Ribavirin) 0 (Antiviral Agents) 415SHH325A (Adenosine Monophosphate)
تواريخ الأحداث:	Date Created: 20240414 Date Completed: 20240702 Latest Revision: 20240702
رمز التحديث:	20240702
DOI:	10.1111/bph.16344
PMID:	38616133
قاعدة البيانات:	MEDLINE

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تدمد:	1476-5381
DOI:	10.1111/bph.16344