Broad-Spectrum Antiviral Efficacy of 7-Deaza-7-Fluoro-2'-C-Methyladenosine Against Multiple Coronaviruses In Vitro and In Vivo

Abstract

The Coronaviridae family has been implicated in several major epidemics over the past two decades, including those caused by SARS-CoV, MERS-CoV, and, most recently, 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 effectively reduced the viral load in the 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 calculated Selectivity Index (SI) of 6.2. In vivo investigations further 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 transgenic K18-hACE2 mouse model infected with SARS-CoV-2--DFMA administration significantly reduced viral loads in the lungs of infected mice. Additionally, DFMA mitigated inflammatory responses in all models 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 current and future coronavirus outbreaks. Further research is warranted to elucidate its mechanism of action and evaluate its efficacy in clinical settings. ImportanceCoronaviruses have caused significant outbreaks over the past two decades. Since 2020, COVID-19 has resulted in millions of deaths and lasting global impacts. The limited availability of effective antivirals and the viruss ability to mutate and evade vaccines and monoclonal antibody therapy emphasize the urgent need for new treatments. This study investigates DFMA, a promising antiviral candidate, targeting SARS-CoV-2 and two related coronaviruses.Our promising results demonstrated significant antiviral activity of DFMA, not only against SARS-CoV-2 but also against other similar coronaviruses, indicating potential future use against COVID-19 and other possible coronavirus-related diseases.