Mpro and PLpro are cysteine proteases responsible for the cleavage of viral polypeptides into functional proteins for virus replication and packaging within host cells.24 These enzymes represent the best characterized drug targets among coronaviruses and are currently the focus of attention among scientists seeking novel coronavirus small molecule therapeutics.25 Mpro is shared by all coronavirus genera and has similarity to the 3Cpro of the Enterovirus genus in the picornavirus family.24 Mpro contains a Cys···His catalytic dyad with an additional α-helical domain involved in the dimerization of the protease, which is essential for its catalytic activity.25 The enteroviral 3Cpro functions as a monomer featuring a classical Cys···His···Glu/Asp catalytic triad.24 Yet, they share the almost absolute requirement for Gln in the P1 position of the substrate and space for only small residues such as Gly, Ala, or Ser in the P1′ position. Since no human proteases with a similar cleavage specificity are known, it may be possible to identify highly selective Mpro/3Cpro inhibitors, which display minimal inhibition of host proteases.26 The 3-D structures of unliganded SARS-CoV-2 Mpro and of its complex with a peptidomimetic α-ketoamide inhibitor (11r) have been solved26 and were used to support the design of an optimized derivative (13b) through docking studies (Figure S2). α-Ketoamides can interact with the catalytic center of Mpro through two hydrogen bonding interactions rather than only one as with other warheads such as aldehydes or Michael acceptors.24 Nucleophilic attack of the α-keto group by the catalytic Cys residue results in reversible formation of a thiohemiketal. These α-ketoamides feature a 5-membered rigid γ-lactam as a mimic of the P1 residue, glutamine, required for Mpro specificity, with the advantage of reducing the loss of entropy upon binding.24 Follow up optimization efforts guided by docking to the SARS-CoV-2 Mpro co-crystal structure with 11r, included incorporation of the P3-P2 amide bond into a pyridone ring as in 13a. The resulting half-life of 13a in plasma was enhanced by 3 fold relative to 11r, in vitro kinetic plasma solubility improved by a factor of ∼19 and thermodynamic solubility by a factor of ∼13. 13a inhibited purified recombinant SARS-CoV-2 Mpro, SARS-CoV Mpro, and MERS-CoV Mpro in the submicromolar range.26 Modification of the P1′ and P3 moieties of 13a afforded an optimized derivative 13b which was crystallized with SARS-CoV-2 Mpro (PDB: 6Y2G and 6Y2F). Both 13a and 13b displayed good stability in mouse and human microsomes. 13b (3 mg/kg) showed longer t1/2, tmax, and residence time compared to 13a (20 mg/kg) in CD-1 mice. Both compounds showed lung tropism which is thought to be beneficial. While the development of these ketoamides into clinical candidates requires additional safety studies, the availability of their crystal structures is of great importance in facilitating the discovery and development of other Mpro inhibitors. One of the suggested agents for testing is the previously reported Rhinovirus and SARS-CoV Mpro inhibitor clinical candidate rupintrivir (AG-7088) (Figure S2). In addition, other groups recently reported Mpro crystal structures with inhibitors such as the peptidomimetic Michael acceptor N3 (PDB: 6LU7) and the reversible inhibitor X77 (PDB: 6W63) (Figure S2).27 A large array of Mpro crystal structures with multiple covalent and noncovalent fragments were solved through an exceptionally large screen with vast opportunities for fragment growing and merging. The cryo EM structure of SARS-CoV-2 RdRp was recently solved, showing nearly an identical sequence to its SARS-CoV homologue.28 RdRp should be another high priority target for therapeutic intervention given that lead inhibitors such as remdesivir already exist.