Broad-Spectrum Antiviral Efficacy of 7-Deaza-7-Fluoro-2'-C-Methyladenosine Against Multiple Coronaviruses In Vitro and In Vivo
Broad-Spectrum Antiviral Efficacy of 7-Deaza-7-Fluoro-2'-C-Methyladenosine Against Multiple Coronaviruses In Vitro and In Vivo
Chaves, I. d. M.; de Souza, F. R. O.; Queiroz-Junior, C. M.; Oliveira, L. C.; Andrade, A. C. d. S.; Costa, V. R. d. M.; Teixeira, D. C.; Santos, F. R. d. S.; Fonseca, T. C. M.; Lacerda, L. d. S. B.; Pereira, R. d. D.; Pimenta, J. C.; Amblard, F.; Schinazi, R. F.; Teixeira, M. M.; Costa, V. V.
AbstractThe Coronaviridae family has been implicated in several epidemics over the past two decades, including those caused by SARS-CoV, MERS-CoV, and SARS-CoV-2. The COVID-19 pandemic, driven by SARS-CoV-2, has led to over seven million deaths worldwide and has been associated with prolonged symptoms, chronic sequelae, and substantial socioeconomic disruptions. The limited availability of effective antiviral treatments, coupled with the ability of coronaviruses to mutate and evade immune defenses, underscores the urgent need for innovative antiviral agents. This study explores the efficacy of the nucleoside analogue DFMA as a potential antiviral agent against multiple Coronaviridae family members, including SARS-CoV-2 and two strains of murine hepatitis viruses (MHV-3 and MHV-A59). In vitro analyses demonstrated that DFMA reduced the viral load in supernatant of infected cells and enhanced cell viability for both MHV-3 and MHV-A59. Against SARS-CoV-2, DFMA showed a significant reduction in viral load, with a Selectivity Index (SI) of 6.2. In vivo investigations confirmed the antiviral potential of DFMA. In three distinct murine models; a severe COVID-19 model using MHV-3, a mild COVID-19 model employing MHV-A59, and a K18-hACE2 model infected with SARS-CoV-2-DFMA administration significantly reduced viral loads in the lungs of infected mice. Additionally, DFMA mitigated inflammatory responses by lowering levels of key inflammatory mediators, such as CXCL1, CCL2, and IL-6. These findings suggest that DFMA possesses broad-spectrum antiviral activity against coronaviruses and may serve as a promising therapeutic candidate for coronavirus outbreaks. Further research is warranted to elucidate its mechanism of action and evaluate its efficacy in clinical settings.