Peptidyl HMK inhibitors and their corresponding ethers have been designed as potent reversible cysteine protease inhibitors of cathepsin K34 and cruzain.43 High-resolution crystal structures of two such inhibitors complexed with cruzain highlighted the presence of a strong hydrogen bond between the catalytic His and the α-hydroxyl moiety of the inhibitor but interestingly no covalent bond between the active-site Cys and the ketone pharmacophore. Utilizing the crystal structure of 28 in complex with SARS CoV-1 3CLpro, molecular modeling of an HMK-based design indicated the potential for establishing a covalent bond between the sulfur of the active-site cysteine (Cys145) and the HMK carbonyl as well as hydrogen bond interactions between catalytic His41 and the terminal hydroxy moiety. Additionally, the structure of 28 suggested the possibility to increase the lipophilic filling of the deep hydrophobic S2 pocket as a strategy to increase binding affinity. To evaluate these structure-based observations, a series of reversible HMK inhibitors containing P2 diversity were prepared as depicted in Table 3.