Protease Inhibitors that Bind to One Side of the Active Site

Protease Inhibitors that Bind to One Side of the Active Site 

The very first examples were some simple boronic acid compoimds [5, 6]. For example, phenylboronic acid and substituted phenylboronic acids were found to be strong competitive inhibitors of subtilisin and chymotrypsin [6]. More recendy, boronic acids have been used for the synthesis of inhibitors against thrombin [50,51], lactamases [52], dipeptidyl peptidases [53], and others [54, 55]. In this section, thrombin inhibitors will be used as examples. The rest will be summarized in a table at the end of the section. 

Flgure13.2 Binding of compound 8 to thrombin. Three key interactions are shown (a) interaction with the amino side-chain of Asp-189 in the SI specificity pocket (b) tetrahedral complex formed between the hydroxyl group 

There have also been efforts in designing selective thrombin inhibitors by varying the PI position. For example, incorporation of m-cyano-substituted phenylalanine boronic acid analogues into R-(D)Phe-Pro-OH dipeptides produced several highly effective thrombin inhibitors such as H-(D)Phe-Pro-boroPhe(m-CN)-OH [62]. The cyano group enhances binding by several orders of magnitude. Because of its struc- 

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