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hibitors (Figure 11) include renin inhibitors, 41 [47] and 42 [48]; HIV protease inhibitors 43 [49] and 44
[50]; angiotensin-converting enzyme inhibitors 45 [51] and 46 [52]; collagenase inhibitor, 47 [53];
gelatinase inhibitor, 48 [54], stromelysin inhibitor, 49 [55]; elastase inhibitor, 50 [56]; thrombin
inhibitors, 51 [57] and 52 [58]; and interleukin-converting enzyme inhibitor, 53 [59]. In general, the
design of protease inhibitors has focused on both the natural substrate structure and the mechanism of
substrate cleavage to provide “first-generation” inhibitors. Also, these initial leads are typically peptide
scaffold-based to provide the possibility for β-sheet conformation, which may permit “extensive” Hbonding
between the backbone amide groups of the inhibitor and complementary H-bond donor or
acceptor groups of the enzyme active site. Furthermore, the traditional approach to designing protease
inhibitors includes the substitution of nonhydrolyzable amide surrogates (see below Figure 4) at the P1- P1' cleavage site. Specificity to a particular protease may sometimes be extrapolated directly from the
primary structure of the substrate (e.g., human renin substrate specificity is conferred from the
angiotensinogen N-terminal octapeptide sequence ~His6-Pro-Phe-His-Leu Val-Ile-His13~ in which
refers to the cleavage site). In many cases substitution of the scissile amide (substrate) by a “transition
state” bioisosteres or an electrophilic ketomethylene moiety have provided tight-binding “first
generation” pseudopeptide inhibitor leads.
One example of protease inhibitor design that illustrates the peptide scaffold-based approach is that for
HIV protease inhibitors. Albeit over the past several years HIV protease inhibitor research has become a
highly advanced example of iterative structure-based drug design (see below), the first discoveries of
pseudopeptide and peptidomimetic inhibitors of this aspartyl protease were not made with knowledge of
the 3D structure of the target enzyme. Specifically, the natural product pseudopeptide pepstatin (Figure
12), a typical inhibitor of the aspartyl protease family of enzymes, was determined to be weakly potent
against HIV-1 protease [60]. Relative to pepstatin, the central P 1-P 1' statine (i.e., Sta or
LeuΨ[CH(OH)]Gly) moiety was further evaluated within the context of an “optimized” N- and Cterminal
amino acid sequence using a chemical-library strategy [61]. As shown in Figure 12, a resultant
pseudo-tetrapeptide Ac-Trp-Val-Sta-D-Leu-NH 2 was found to be a relatively potent HIV protease
inhibitor. In another approach, a designed renin inhibitor (55; Figure 12) was determined to be a highly
potent HIV protease inhibitor [62]. Further optimization studies led to the discovery [49] of the first
bonafide peptidomimetic inhibitor of HIV protease (Tba-ChaΨ[CH(OH)CH 2] Val-Ile-Amp; 43) of HIV
protease. This compound (43) provided the first evidence of cellular anti-HIV activity and, therefore,
supported proof-of-concept studies related to the therapeutic significance of targeting HIV-1 protease.
Replacement of the peptide scaffold by the pyrrolidinone-type β-sheet mimetic 28 in a
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