Evaluating Z-FA-FMK, a host cathepsin L protease inhibitor, as a potent and broad-spectrum antiviral therapy against SARS-CoV-2 and related coronaviruses

Even though the World Health Organization announced the end of the COVID-19 pandemic as a global public health emergency on May 5, 2023, SARS-CoV-2 continues to pose a significant health threat worldwide, resulting in substantial numbers of infections and fatalities. This study investigated the antiviral potential of Z-FA-FMK (FMK), a novel host cathepsin L protease inhibitor, against SARS-CoV-2 infection using both in vitro and in vivo models. In vitro assessments of FMK against a diverse set of SARS-CoV-2 strains, including the Wuhan-like strain and nine variants, demonstrated potent inhibition with EC50 values ranging from 0.55 to 2.41 & mu;M, showcasing similar or superior efficacy compared to FDA-approved antivirals nirmatrelvir (NTV) and molnupiravir (MPV). In vivo experiments using orally administered FMK (25 mg/kg) in SARS-CoV-2-infected K18 hACE2 transgenic mice revealed improved survival rates of 60% and accelerated recovery compared to NTV and MPV treatments. Additionally, FMK displayed a longer half-life (17.26 & PLUSMN; 8.89 h) than NTV and MPV in the mouse model. Due to its host-targeting mechanism, FMK offers potential advantages such as reduced drug resistance and broadspectrum antiviral activity against multiple coronaviruses. These findings indicate that FMK may serve as a promising candidate for further clinical evaluation in the fight against SARS-CoV-2.

Automated summary

Although the COVID-19 pandemic has been declared a global public health emergency by the World Health Organization on May 5, 2023, SARS-CoV-2 remains a significant health threat worldwide, causing numerous infections and deaths. This study investigated the antiviral potential of a novel protease inhibitor called Z-FA-FMK (FMK) against SARS-CoV-2 infection using both in vitro and in vivo models. The results showed that FMK demonstrated potent inhibition against various SARS-CoV-2 strains with similar or superior efficacy compared to FDA-approved antivirals. In vivo experiments in mice also revealed improved survival rates and accelerated recovery with FMK treatment.