Peptide aldehydes 9a-c were identified as extremely potent CatL inhibitors (Figure ). The representatives with the preselected cinnamoyl and 1H-indole-2-carbonyl capping groups, i.e., 9a and 9b, exhibited Ki values of 2.67 nM and 1.76 nM. The introduction of two methoxy groups at the cinnamoyl moiety slightly reduced CatL inhibitory activity (9c vs. 9a). Aside from the electrophilic reactivity of the warhead, the other structural components contribute to the binding affinity of the extraordinarily potent CatL inhibitors 9a and 9b. The side chains of phenylalanine and leucine are expected to occupy the S1 and S2 specificity pockets, respectively, and the N-terminal capping group is thought to be accommodated in the S3 binding site. Peptide aldehyde 9b also showed inhibition of SARS-CoV-2 M pro , albeit in the micromolar range (Figure ). The nitrile group was introduced in place of the aldehyde in the following set of compounds (11a-h) with various P3 moieties. Since the Leu-Phe portion was kept constant, these compounds allowed for an optimization of the P3 moiety. Compound 11a with the unsubstituted cinnamoyl group demonstrated good CatL inhibition in contrast to its 3,5dimethoxy derivative 11c, likely because of an unfavorable steric interaction. The indole derivative 11b was a somewhat weaker inhibitor than 11a. The three phenoxyacetyl derivatives 11d-f demonstrated effective CatL inhibition with Ki values between 111 nM and 870 nM. Fascinatingly, the cyclic form of the phenoxyacetyl derivative 11g showed excellent CatL inhibition with a Ki value of 9.56 nM (Figure ), indicating that rigidization accounted for a favorable binding mode of 11g. None of the peptide nitriles inhibited SARS-CoV-2 M pro .