ABSTRACT
The unprecedented pandemic of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which leads to COVID-19, is threatening global health. Over the last 2 years, we have witnessed rapid progress in research focusing on developing new antiviral vaccines and drugs, as well as in academic and clinical efforts to understand the biology and pathology of COVID-19. The roles of proteases among master regulators of SARS-CoV-2 invasion and replication and their pivotal roles in host defence against this pathogen, including programmed cell death, have not been well established. Our understanding of protease function in health and disease has increased considerably over the last two decades, with caspases, matrix metalloproteases, and transmembrane serine proteases representing the most prominent examples. Therefore, during the COVID-19 pandemic, these enzymes have been investigated as potential molecular targets for therapeutic interventions. Proteases that are responsible for SARS-CoV-2 cell entry and replication, such as TMPRSS2, ACE2 or cathepsins, are screened with inhibitor libraries to discover lead structures for further drug design that would prevent virus multiplication. On the other hand, proteases that orchestrate programmed cell death can also be harnessed to enhance the desired demise of infected cells through apoptosis or to attenuate highly inflammatory lytic cell death that leads to undesired cytokine storms, a major hallmark of severe COVID-19. Given the prominent role of proteases in SARS-CoV-2-induced cell death, we discuss the individual roles of these enzymes and their catalytic interactions in the pathology of COVID-19 in this article. We provide a rationale for targeting proteases participating in cell death as potential COVID-19 treatments and identify knowledge gaps that might be investigated to better understand the mechanism underlying SARS-CoV-2-induced cell death.