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Document Page 576 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_576.html [4/9/2004 1:11:16 AM]
Document Figure 12 Peptide scaffold-based design strategies: HIV protease inhibitors http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_577.html (1 of 2) [4/9/2004 1:11:42 AM] Page 577
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Document Chris Tantillo. The work i
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Document Table 1 Approval Indicatio
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Page 743 and 744: Document Page 603 hydroxymethyl sub
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Document Acknowledgments Page 620 I
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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