Fitness-Dependent, Mild Mutagenic Activity of Sofosbuvir for Hepatitis C Virus

Martínez-González, Brenda; Gallego, Isabel; Gregori, Josep; Soria, María Eugenia; Somovilla, Pilar; Ávila, Ana Isabel de; García-Crespo, Carlos; Durán-Pastor, Antoni; Briones, Carlos; Gómez, Jordi; Quer, Josep; Domingo, Esteban; Perales, Celia

doi:10.1128/aac.00394-23

Cited by 1 publication

(1 citation statement)

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“…Also, sofosbuvir increased the frequency of C ! U transitions in HCV RNA, thus acting as a mild mutagen for this virus (Martínez-González et al, 2023). In the case of RDV, a mutagenic activity may be mediated by the interconversion between their amino and imino tautomers (Jena, 2020), together with a proportion of incorporated RDV molecules that fail to terminate chain elongation (Wang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

García‐Crespo,

de Ávila,

Gallego

et al. 2024

British J Pharmacology

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Background and PurposeThere 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 ApproachThe 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 ResultsRemdesivir 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 ImplicationsSARS‐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.

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Section: Discussionmentioning

confidence: 99%