2.8. Conclusions. In summary, we developed a new class of small-molecule peptidomimetics based on the virtual screening of a kinase inhibitor collection for their inhibition of human cathepsins, the host cysteine proteases involved in the pathogenesis of SARS-CoV-2. The molecular design included three fragments, out of which the N-terminal capping group and the C-terminal warhead were diversified, and the central Leu-Phe dipeptide fragment was maintained. This approach resulted in a variety of highly effective CatL and CatS aldehyde-type inhibitors, including those with low nanomolar to subnanomolar Ki values, i.e., 9a-c. Compounds with the nitrile warhead (11a and 11d-g) have also been identified as dual CatL and S inhibitors. Most inhibitors were selective for CatL and S over human CatB. The cellular role of human CatS for viral infection is much less defined than that of CatL. However, recent studies underlined that CatS contributes to acute lung injury and may represent a novel therapeutic target to combat respiratory diseases. Hence, CatS inhibition may be a desirable feature of anti-SARS-CoV-2 drugs. In general, cathepsin inhibition was not accompanied by similarly pronounced M pro inhibition. When subjecting selected compounds to an evaluation of their antiviral properties, we identified certain peptidomimetics that effectively prevented SARS-CoV-2 infection in Calu-3 cells. The peptide nitrile 11e showed high antiviral activity with an EC50 value of 35.1 nM, displayed no cytotoxicity, and exhibited high metabolic stability, making it a suitable drug for further preclinical development.