Selecting a starting structure for inhibitor design. The design of the cyclic peptide inhibitor begins with the X-ray crystallographic structure of SARS-CoV M pro (C145A) [Protein Data Bank (PDB) ID: 5B6O]. The SARS-CoV M pro is 96% identical to the SARS-CoV-2 M pro , and thus provides a good starting point for the design of inhibitors of SARS-CoV-2 M pro . In this crystal structure, the C-terminal fragment of one M pro molecule extends into the active site of an adjacent M pro molecule. The C-terminal fragment would normally be cleaved by SARS-CoV M pro , and thus the inactive C145A mutant provides a snapshot of the enzyme bound to one of its substrates. Molecules that mimic the C-terminal fragment, but are resistant to proteolysis, may serve as inhibitors that block viral replication.