https://doi.org/10.15255/KUI.2003.023
Published: Kem. Ind. 53 (11) (2004) 495–504
Paper reference number: KUI-23/2003
Paper type: Review
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Peptide Mimetics: Why and How?

I. Jerić

Abstract

Peptides and proteins are of key importance in many chronic and infectious disorders. Prion diseases are result of conformational changes of a protein, while development of Alzheimer disease is associated with deposition of β-amyloid peptides in insoluble form. Autoimmune diseases are characterized by recognition dysfunction, self-peptides being attacked by immune system as foreign molecules. At the same time, peptides as therapeutic agents are of very limited use. Peptides are highly flexible molecules, easily degraded by proteases and usually too polar to pass membranes that separate them from their targets in the cells (Fig. 1). Considerable efforts have been put in designing the compounds with improved bioavailability and capability to mimic peptide functions, resulting in heterogeneous class of compounds known as peptidomimetics. The very first steps in peptidomimetic design were based on simple N- or C-terminus modifications, single amino acid replacement or chiral changes (Fig. 2). Next, cyclization reactions are very useful in peptidomimetic synthesis. “HeadÆtail” cyclizations result in many impressive structures with promising conformational features (Figs. 3 and 4). There are also interesting examples of cyclic peptides and peptidomimetics comprising sugar moiety (Fig. 5). Ring-closing metathesis is another useful method for the preparation of both small and macrocyclic rings (Fig. 6). Peptide bond modifications brought a number of compound classes, like peptoids, retropeptoids, urea-peptidomimetics and sulfonamide peptides/ peptoids (Fig. 7). Sugar amino acids offer many possibilities in preparation of peptidomimetics with predictable conformational characteristics (Figs. 9 and 10). On the other hand, β-amino acid based peptidomimetics proved to be highly proteases-resistant, conformationally well-defined and potentially attractive inhibitors, peptide- like vaccines and antimicrobial agents.

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Keywords

modified peptides, peptidomimetics