Fig. 23.28 Crystallographically determined binding mode of nirmatrelvir 23.61 to the SARS-Cov-2 Mpro major protease. The nanomolar inhibitor was optimized for stability and oral bioavailability from a previously discovered peptide analog 23.60 via several design steps. Nirmatrelvir binds covalently via its nitrile group to the catalytic Cys 145 and occupies the specificity pockets S1, S2, and S3 with its side chains. The oxyanion hole is formed by the NH groups of Gly 143 and Cys 145.