ABSTRACT
Since its outbreak, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused one of the most severe pandemics in recent history and had enormous effects on the lives of millions of people worldwide. Peptidases, both viral and host, have been described as critical enzymes in mechanisms underlying SARS-CoV-2 infection and replication. Among host peptidases, the involvement in activation of viral glycoproteins and processing of the SARS-CoV spike protein has been described for endosomal/lysosomal cysteine peptidases cathepsins B and L, which therefore represent promising targets for development of effective drugs for treatment of COVID-19. To date, a large number of cathepsin B and L inhibitors have been identified and evaluated for treatment of various pathological processes. In this study, we have evaluated well-established known potent selective and reversible cathepsin B inhibitors for their potential to act against SARS-CoV-2. Cathepsin B inhibitors showed significant activity in preventing viral entry and replication of SARS-CoV-2. Next, we observed that antiviral activity of compounds was dependent on the cell type and correlated well with the intracellular amount of the targeted cathepsin. Taken together, we have demonstrated the important role of host cysteine peptidase cathepsin B during SARS-CoV-2 infection and identified its inhibitors as potential new therapeutic agents for treatment of SARS-CoV-2 infection.