The successful entry of the virus is dependent on the cleavage and activation of its spike protein by host cell proteases. The membrane-bound transmembrane serine protease 2 (TMPRSS2) is the main processing enzyme whose activity promotes direct endocytic cell entry via membrane fusion of the virus and the host cell. The endosomal entry constitutes an alternative route of virion uptake. It is followed by S protein priming within the S1 domain, a process that occurs in the acidic endosomal-lysosomal compartment, where TMPRSS2 is not catalytically competent. Here, the cleavage of the SARS-CoV-2 S protein is catalyzed by human lysosomal cathepsins (Cats). In particular, CatL has a crucial role in SARS-CoV-2 infection. It effectively cleaves the SARS-CoV-2 S protein, enhancing virus entry. Overexpression of CatL during COVID-19 was correlated with the progression and severity of the disease. Furthermore, the expression of CatL was upregulated by interleukin-6 (IL-6), a surrogate proinflammatory marker for severe COVID-19 disease with a poor prognosis. This dual role in the viral entry and the progression of excessive COVID-19 pathology led to the recognition of cathepsins as targets against SARS-CoV-2. Noteworthy, in the Omicron variant of SARS-CoV-2, spike region mutations to basic amino acids caused reduced spike cleavage by TMPRSS2 and thus a decrease in direct host cell entry via membrane fusion. This is compensated by the increased use of the endosomal entry pathway and consequent cleavage by cathepsins. Several inhibitors targeting cathepsins have been reported for their anti-SARS-CoV-2 activity and have been proposed as a possible therapeutic option to combat COVID-19 (Figure ). The pan-cathepsin inhibitor E-64d prevented the SARS-CoV-2-S-driven cell entry when it was co-administered with the TPMRSS2 inhibitor camostat mesylate. The highly potent CatS/L inhibitor K777 and the picomolar cathepsin L inhibitor gallinamide A reduced SARS-CoV-2 infections in a number of cell lines. Both, K777 and gallinamide A, were inactive against M pro . The fluoromethylketone Z-FA-FMK, a potent, irreversible inhibitor of a number of cysteine proteases, including cathepsins B, L, and S, with less pronounced activity against M pro , 31 has demonstrated excellent anti-SARS-CoV-2 activity in vitro and in vivo. Moreover, the strong cathepsin inhibitor calpeptin, a Z-protected leucine-norleucine-derived aldehyde, was active in SARS-CoV-2-treated hamsters. 33 The growing appeal of cathepsins as therapeutic targets for COVID-19 served as the impetus for our research. In the present study, initiated by a virtual screening of the Tübingen Kinase Inhibitor Collection (TüKIC) for inhibition of CatL, we designed and synthesized a series of tailored peptidomimetics and characterized their inhibitory activity against CatL, B, S, and M pro . We discovered highly potent inhibitors, and based on these findings, their antiviral activity was determined. Docking studies were performed to obtain insights into their molecular interaction with the target protease CatL. Furthermore, the metabolic stability of the test compounds was investigated and demonstrated.