Peptidomimetic templates

Smith AB, Hirschmann R, Pasternak A et al (1997) An artificial antiparallel p-sheet containing a new peptidomimetic template. J Med Chem 40 2440-2444... 

They can serve as templates or useful scaffolds from which peptidomimetic drugs with enhanced activity can be designed. ... 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

R. M. Jones, P. D. Boatman, G. Semple, Y.-J. Shin, S. Y. Tamura (2003). Clinically validated peptides as templates for de novo peptidomimetic drug design at G-protein-coupled receptors. Curr. Opin. Pharmacol. 3 530-543. 

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 above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Specific examples of peptidomimetics which illustrate peptide scaffold- and nonpeptide template-directed drug-design strategies as applied to protease in-... 

Scheme 3 Synthesis of a Peptidomimetic Incorporating the 2,8-Dibenzofuran-Based Template 11...

The nucleation of parallel (3-sheet structure via metal ion chelation in aqueous solution was investigated by incorporating an ethylene glycol spacer between a dibenzofuran-4,6-dipro-panoic acid template and the two peptide strands (Scheme 6).[7 The flexibility of the ethylene glycol spacer allows the peptide to sample a variety of largely unordered conformations in the absence of metal ions. Upon binding of palladium(II), nickel(II), or copper(II) ions, the peptidomimetic adopts a well-defined (3-sheet conformation as discerned from biophysical and spectroscopic studies (i.e., CD, IR absorption, and H NMR spectrometry).17 The synthesis of the dibenzofuran-4,6-dipropanoic acid template was discussed... 

Scheme 10 Synthesis of Peptidomimetics Incorporating the 6,6 -Bis(acylamino)-2,2 -bipyridine-Based Template 3-41...

Using a solution segment condensation reaction analogous to that described above it is possible to obtain a maximal 50% yield of a monosubstituted template using one equivalent of peptide nucleophile. The monosubstituted product can be purified away from the unsubstituted and disubstituted templates, and subjected to a second coupling reaction with a different peptide nucleophile affording an unsymmetrical peptidomimetic, albeit in modest yield. 

Scheme 11 Synthesis of Peptidomimetics Incorporating the 4,6-Dibenzofuran-Based Template To Give Asymmetrical Parallel (1-Sheet Sequences 21...

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