Aspartic acid transition state analogs

The strategy of designing saquinavir was based on the transition-state mimetic concept, an approach that has been used successfully in the design of potent inhibitors of renin and other aspartic proteases [10]. From the variety of nonscissile transition-state analogs of a dipeptide, the hydroxyethylamine mimetic was selected because it most readily accommodates the amino acid moiety characteristic of the Phe-Pro and Tyr-Pro cleavage sequence of the... 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

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