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compounds that utilize similar transition-state analogs and retain at least one peptide bond with a side
chain corresponding to a naturally occurring amino acid. Several compounds from this group have
excellent pharmacokinetic and antiviral properties and, in fact, all three HIV PR inhibitors approved for
clinical use (saquinavir, ritonavir, and indinavir) belong to this class of compounds. The last and the
smallest group of HIV PR inhibitors has a distinct nonpeptidic character. Compounds from this class
were discovered either by screening libraries of existing compounds or by structure-based de novo
design. Illustrative examples of inhibitors belonging to all three classes and a brief description of the
discovery of selected compounds are presented below.
D. Peptidic Inhibitors of HIV PR
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The concept of peptidic inhibitors of HIV PR can be exemplified by the crystal structure of the statinecontaining
peptidic compound AG1002 (Figure 3) [23]. In AG1002, the statine moiety replaces the
scissile dipeptide while the flanking amino acids were derived from the natural substrate cleaved by HIV
PR. The inhibitor binds to the active site in an extended conformation with the central hydroxyl group of
the statine moiety forming hydrogen bonds with the active-site aspartic acids 25/25'. The peptidic
backbone and the side chains of the
Figure 3
Stereo view of the peptidic inhibitor AG1002 bound to the active site of HIV PR.
The distribution of the specificity subsites S and S' is similar to that shown in
Figure 2. The boundaries of the HIV PR active site are indicated by the dotted
surface.
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