tetano
Editor, Senior Moderator
Br J Pharmacol
. 2024 Apr 14.
doi: 10.1111/bph.16344. Online ahead of print. Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture
Carlos García-Crespo[SUP] 1 [/SUP], Ana Isabel de Ávila[SUP] 1 [/SUP], Isabel Gallego[SUP] 1 [/SUP], María Eugenia Soria[SUP] 1 2 [/SUP], Antoni Durán-Pastor[SUP] 3 [/SUP], Pilar Somovilla[SUP] 1 4 [/SUP], Brenda Martínez-González[SUP] 2 3 [/SUP], Javier Muñoz-Flores[SUP] 5 [/SUP], Pablo Mínguez[SUP] 6 7 8 [/SUP], Llanos Salar-Vidal[SUP] 2 9 [/SUP], Mario Esteban-Muñoz[SUP] 2 [/SUP], Elizabeth Cañar-Camacho[SUP] 2 [/SUP], Cristina Ferrer-Orta[SUP] 10 [/SUP], Sonia Zuñiga[SUP] 3 [/SUP], Isabel Sola[SUP] 3 [/SUP], Luis Enjuanes[SUP] 3 [/SUP], Jaime Esteban[SUP] 2 9 [/SUP], Ricardo Fernández-Roblas[SUP] 2 9 [/SUP], Ignacio Gadea[SUP] 2 9 [/SUP], Jordi Gómez[SUP] 11 [/SUP], Nuria Verdaguer[SUP] 10 [/SUP], Esteban Domingo[SUP] 1 [/SUP], Celia Perales[SUP] 2 3 [/SUP]
Affiliations
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.
Keywords: COVID‐19 therapy; Quasi‐species; error catastrophe; lethal mutagenesis; virus diversity.
. 2024 Apr 14.
doi: 10.1111/bph.16344. Online ahead of print. Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture
Carlos García-Crespo[SUP] 1 [/SUP], Ana Isabel de Ávila[SUP] 1 [/SUP], Isabel Gallego[SUP] 1 [/SUP], María Eugenia Soria[SUP] 1 2 [/SUP], Antoni Durán-Pastor[SUP] 3 [/SUP], Pilar Somovilla[SUP] 1 4 [/SUP], Brenda Martínez-González[SUP] 2 3 [/SUP], Javier Muñoz-Flores[SUP] 5 [/SUP], Pablo Mínguez[SUP] 6 7 8 [/SUP], Llanos Salar-Vidal[SUP] 2 9 [/SUP], Mario Esteban-Muñoz[SUP] 2 [/SUP], Elizabeth Cañar-Camacho[SUP] 2 [/SUP], Cristina Ferrer-Orta[SUP] 10 [/SUP], Sonia Zuñiga[SUP] 3 [/SUP], Isabel Sola[SUP] 3 [/SUP], Luis Enjuanes[SUP] 3 [/SUP], Jaime Esteban[SUP] 2 9 [/SUP], Ricardo Fernández-Roblas[SUP] 2 9 [/SUP], Ignacio Gadea[SUP] 2 9 [/SUP], Jordi Gómez[SUP] 11 [/SUP], Nuria Verdaguer[SUP] 10 [/SUP], Esteban Domingo[SUP] 1 [/SUP], Celia Perales[SUP] 2 3 [/SUP]
Affiliations
- PMID: 38616133
- DOI: 10.1111/bph.16344
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.
Keywords: COVID‐19 therapy; Quasi‐species; error catastrophe; lethal mutagenesis; virus diversity.