ABSTRACT
Peptides and proteins have limited usefulness as drug candidates due to their poor bioavailability and high cost of manufacture. As a consequence smaller peptidomimetic molecules are usually sought to reproduce the biological properties of peptides but with higher metabolic stability and bioavailability. There are a number of current approaches to peptidomimetics, ranging from designing conformationally constrained molecules that structurally mimic the folded backbone main chain structures adopted by peptides (e.g. helices, turns, strands, sheets) to non-peptidic scaffolds that completely replace peptide main chains but similarly position and orientate peptide side chains or their surrogates for optimal interactions with receptors. The former category represents a minimalist approach to drug design, restricting changes made to bioactive peptides to the fewest required for improving bioactivity while achieving structural and functional mimicry of a peptide surface. The latter category
includes natural product peptidomimetics as well as designed compounds containing three dimensional non-peptidic scaffolds that appropriately project functionality for attaching structural or functional mimetics of peptide side chains. We illustrate these approaches ahead with a limited number of classic examples from the different categories of backbone and side chain peptidomimetics, but focus particularly on new approaches to developing molecules that mimic secondary structures of proteins.
