Peptide ligand design

The design of such low-molecular weight compounds that inhibit or mimic the action of a naturally occurring protein epitope or peptide ligand is a con-... 

Fig. 9. Peptidomimetic design principle of SH2 antagonists derived from a fragmentation of the native peptide ligand. The lead finding efforts discussed in Sect. 3 are classified according to the modules given above the peptide lead sequence...

The Novartis group used the X-ray structure of a Grb2-peptide complex [68] as the structural basis for a design attempt that yielded entirely new non-peptide SH2 domain ligands [164]. As mentioned several times throughout this contribution, the interaction of the pTyr sidechain and the Asn sidechain in pTyr+2 position of the peptide ligand have been identified as key elements for molecular recognition (see Fig. 10). The obvious relevance of these two sidechain functionalities allowed the definition of a minimal pharmacophore pattern that... 

II. Peptide Ligand Lead Discovery and Structure-Based Drug Design... 

A second example is that involving the use of a glucopyranoside nonpeptide template by Hirschmann and coworkers [41, 46] for systematic functionalization to create novel peptidomimetics for the somatostain (SRIF) and substance-P (NKj) receptors. As illustrated in Figure 10, the cyclic hexapeptide SRIF agonist provided a macrocyclic lead stmcture that was transformed to a glucopyranoside template designed to substitute for a postulated 3 turn about the Tyr-D-Trp-Lys-Thr substructure of the parent peptide ligand. The prototype... 

The most severe problems exist with peptide ligands, and this is particularly the case for the high-throughput screening of peptide libraries. Once an active peptide has been discovered, it will be necessary to design a suitable non-peptide analogue to avoid the problems of poor absorption and sensitivity to peptidases that confound the direct use of peptides as drugs. It will be necessary to know the conformation of the peptide lead. 

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