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The Ile-Pro sequence of CA074, potent covalent-type inhibitor, is necessary to exhibit the specificity for cathepsin B, but not for papain. In order to elucidate how its sequence binds to papain and why such binding does not exhibit the specificity for papain at the atomic level, two CA074-related compounds, 1 (N-(L-3-carboxyloxirane-2-carbonyl)-L-isoleucyl-L-proline) and 2 (N-(L-3-carboxyloxirane-2-carbonyl)-L-isoleucyl-diethylamide), were designed and their structure--inhibitory activity relationship was investigated by the X-ray crystal analyses of the complexes with papain. The Ile-Pro moiety of 1 was located at the S2 and S3 subsites consisting of Val-133, Val-157, and Asp-158 and of Tyr-61, Gly-66, and Tyr-67 residues of papain, respectively, which is in contrast with the binding of CA074 to S'n (n = 1 approximately 2) subsites in the complex with cathepsin B. Although 2 in the complex with papain showed the similar binding pattern to 1, its inhibitory activity was about two-fold higher than of 1, suggesting the importance of tight S3-P3 hydrophobic interaction for the activity. The difference of the substrate specificity between papain and cathepsin B has also been discussed based on the X-ray results of the present and cathepsin B-inhibitor complexes.
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