The X‐ray crystal structure of 123 attached to SARS‐CoV‐1 Mpro highlighted the compound's identical orientation in the pocket to that of established covalent peptidomimetic inhibitors (Figure 31). The compound with an R‐configuration occupied the S3‐S1' subsites of SARS‐CoV‐1 Mpro. Indeed, only (R)‐123 was able to inhibit the Mpro enzyme with an IC50 value of 1.5 µM, while the (S)‐enantiomer was inactive. (R)‐123 inhibited SARS‐CoV‐1 Mpro in a competitive manner (K i, 1.6 µM) with a noncovalent mode of inhibition. (R)‐123 also showed antiviral activity (12.9 µM) in mock infected and SARS‐CoV‐1 infected Vero E6 cells.