Based on the highly potent 1,4‐Michael‐acceptor‐based inhibitor 38, which they had previously developed (see Figure 15), Yang et al. 134  designed a peptide with a new efficient cysteine‐reactive group, using an aldehyde moiety. In addition, the P2‐leucine and the Michael groups of 38 were modified by a cyclohexyl unit and aldehyde group respectively to improve cellular activity. Indeed, the resulting peptide‐aldehyde 41 (Figure 15) showed remarkable activity against SARS‐CoV‐1 and HCoV‐229E Mpro. 134  It displayed promising antiviral activities decreasing viral load by 4.7 log (at 5 µM) for SARS‐CoV‐1 and 5.2 log (at 1.2 µM) for HCoV‐229E. This compound was stable in rat, mouse, and human plasma (even after 120 min, more than 70% of it remained in respective cells).