Peptidomimetic design

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...

These examples clearly prove the viability of a structure-based peptidomimetic design approach for developing non-peptide peptidomimetics for therapeutic interference into protein-protein interaction events. 

Historically, the major focus of peptidomimetic design has evolved from receptor-targeted drug discovery research and has not been directly impacted by an experimentally-determined 3D structure of... 

As in the case of the five-membered proline analogues, besides pipecolic acid (6) as the six-membered homologue of proline, related aza-, oxa-, and thia-analogues are used to mimic the conformationally restricting properties of proline in the peptidomimetic design of bioactive compounds.1202 ... 

F ure 3.28. Peptidomimetics that have been designed based on iterative introduction of constraints into parent peptide and hypotheses concerning receptor-bound conformation. Enkephalin mimetic (388), RGD platelet GPIIb/IIIa receptor antagonists (384,385), thyrohberin [TRH (387)], and somatostatin (383,389).For an overview of recent approaches to peptidomimetic design, see the review by Bursavich and Rich (382). 

An outstanding example in peptidomimetic design evolved from these studies. Truncation and conformational restriction of a reduced isostere of the parent peptide substrate, followed by systematic replacement of the peptide-like side-chains provided the potent non-peptidic inhibitor (111)(Fig. 15.46) (207). This approach highlights the transition from a peptide-derived structure to a compound with no apparent resemblance to the original peptide. 

Selected Syntheses of Peptidomimetics Designed for Specific Target Receptor. .. 1011... 

Ripka, A.S. and Rich, D.H. (1998) Peptidomimetic design. Curr. Opin. Chem. Biol. 2 441-452. 

One need look no further than some of the recent reviews in peptide mimetic chemistry - to see the substantial impact of computational chemistry on this field. For example, the 1993 Symposium-in-Print edition of Tetrahedron, entitled Peptide Secondary Structure Mimetics, contains 19 articles by practitioners involved in peptide mimetic design. The majority of these articles include references to the use of some form of computational chemistry in the research effort. In addition, as a further indication of the commercial interest, even a recent patent dealt with the computational aspects of peptidomimetic design. 

Subsequent to these peptidomimetic design efforts, X-ray crystal structures were obtained of inhibitors from the 3-amino-pyridin-2-one and 5-amino-pyrimidin-6-one classes complexed to These experimental... 

Marchand-Brynaert J, Detrait E, Noiset O, Boxus T, Schneider Y-J, Remade C. Biological evaluation of RGD peptidomimetics, designed for the covalent derivatization of cell culture substrata, as potential promoters of cellular adhesion. Biomaterials 1999 20 1773-82. 

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