Proteins peptidomimetics design

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. 

Peptide Vaccines Peptide vaccines are chemically synthesized and normally consist of 8-24 amino acids. In comparison with protein molecules, peptide vaccines are relatively small. They are also known as peptidomimetic vaccines, as they mimic the epitopes. Complex structures of cyclic components, branched chains, or other configurations can be built into the peptide chain. In this way, they possess conformations similar to the epitopes and can be recognized by immune cells. An in silico vaccine design approach has been used to find potential epitopes. A critical aspect of peptide vaccines is to produce 3D structures similar to the native epitopes of the pathogen. 

Chart 10.1 Four biomimetic modules used in our design of modular polymers (a) strong quadmple H bonding motif to form loops, (b) strong quadmple H bonding motif to form double-closed loop (DCL) modules, (c) peptidomimetic 8-sheet motifs to form DCL modules, and (d) small mechanically stable proteins as domains. 

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. 

Wu T-P, Yee V, Tulinsky A, Chrusciel R, Nakanishi H, Shen R, Priebe C, Kahn M. The structure of a designed peptidomimetic inhibitor complex of oc-thrombin. Protein Engineering 1993 5 471-478. 

Signal-transduction protein-targeted peptidomimetics derived by structure-based drug design... 

However, it was immediately recognized by peptide chemists that, even in the cases where a direct (backbone)peptide -protein(backbone) interaction is not operative, the backbone conformation may dramatically influence the biological response. It is evident that the introduction of new, promising peptidomimetics is based primarily on the combined knowledge of the complementary conformational, topochemical, and electronic properties of the native peptide and of its address (in other words, of the receptor or the active site of the enzyme with which it interacts). Then, the design of peptidomimetics as potential bioactive compounds must take into particular account two structural factors (i) a favorable fit (tertiary structure) with respect to the corresponding complementary spatial situation at the active site (ii) the placement of structural elements (e.g., functional groups, polar and... 

HJ Bohm (1996) Towards the automatic design of synthetically accessible protein ligands peptides, amides and peptidomimetics, J Comput Aided Mol Design 10(4) 265—272... 

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