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The recent discovery of peptidomimetic inhibitors of the serine protease TTP-II (tripeptidyl peptidase-II)
further illustrates the peptide scaffold-based design approach [72]. Specifically, relative to a known TTP-
II cleavage site on the endogenous neuropeptide CCK-8 (i.e., Asp 1-Tyr[SO 3H]-Met arrowd.gif Gly-Trp-
Met-Asp-Phe 8-NH 2) the design of a highly potent inhibitor 61 (Figure 13) was successfully achieved by
iterative structure-based optimization of the P3-P1 sequence. Noteworthy of the relatively simple
structure of the TTP-II inhibitor 61 was that it contains no functional group C-terminal to the P 1 αcarbon.
Such absence of an electrophilic moiety, “transition state” bioisostere, or other type of
nonhydrolyzable amide substituent is rather unique relative to most examples of substrate-based
protease inhibitors.
C. Peptidomimetics: Signal-Transduction Protein Inhibitors and Antagonists
Beyond receptors and proteases exists the rapidly emerging area of signal-transduction protein-targeted
drug discovery research. To date, a multitude of catalytic and noncatalytic proteins have been identified
which are critical components of intracellular signal-transduction pathways. These signal-transduction
proteins provide the molecular basis for communication from extracellular “effectors” (e.g., hormones,
neurotransmitters, growth factors, and cytokines) to stimulate cells in specific and regulated manner.
Signal-transduction pathways often involve protein-protein interactions, including examples of enzymesubstrate
(e.g., kinases, phosphatases, transferases, and isomerases) as well nonenzymatic complex
formation (e.g., “adapter” proteins, exchange factors, and transcription factors). As compared to receptor-
or protease-targeted peptidomimetic drug discovery, there are significantly fewer examples reported in
the field of signal-transduction research. Thus, in several cases peptide ligands (as “prototype
peptidomimetic leads”) will be described to illustrate opportunities for structure-based drug design.
Specific examples which illustrate peptide scaffold- and nonpeptide template-directed drug-design
strategies are shown in Figure 14 and include: Ras farnesyl transferase inhibitors, 62 [73], 63 [74], 64
[75], and 65 [76], Src SH2 domain antagonists, 66 [77], 67 [78], and 68 [79]; and the protein tyrosine
phosphatase PTP1B inhibitor 69 [80].
An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide
scaffold- and nonpeptide template-based approaches is that for the Ras farnesyl transferase inhibitor
discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis
[81]. Substrate sequences for farnesyl transferase have the consensus ~Cys-AA 1-AA 2-Met motif (AA
refers to Val or Ile). Both substrate-based
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