Due to the high similarity between SARS‐CoV‐1 Mpro and SARS‐CoV‐2 Mpro authors speculated that 64 was likely to inhibit the new virus as well. Zhang et al. recently reported this molecule as a SARS‐CoV‐2 Mpro inhibitor with an IC50 value of 0.18 µM. They first resolved the unliganded crystal structure of SARS‐CoV‐2 Mpro (Figure 20), 157  which is largely identical to that of SARS‐CoV‐1 Mpro with a 96% sequence identity. Compound 64 was docked to SARS‐CoV‐2 Mpro, and a series of structural modifications were performed to improve its pharmacokinetic properties. Specifically, masking the P2‐P3 amide bond with the pyridone ring could improve plasma half‐life; and exchanging the lipophilic cinnamoyl residue for the less lipophilic Boc group, could increase plasma solubility and reduce its binding to plasma proteins.