The discovery of the physiological role of a great number of peptides stimulated researchers all over the world towards design and synthesis of peptidomimetics ( or peptide-like molecules). are Leu-enkephalin,Met-kephalin,Angiotensin II, Endothelin, Neuropeptide Y , Substance P,Fibrinogen. Since natural peptides seldom can be used therapeutically as drugs, because of the problems associated with low absorption, rapid metabolism and low oral bioavailability, many efforts aimed to modify the natural sequence of the amino acids of bioactive peptides achieved, very focused effect . Advantages of Peptidomimetics as drugs are (i)Conformationally restrained structures can minimize binding to non-target receptors and enhance the activity at the desired receptor.(ii) Addition of hydrophobic residues and/or replacement of amide bonds results in better transport properties through cellular membranes.(iii). Isosteres, retro-inverso peptides, cyclic peptides and non-peptidomimetics all reduce the rate of degradation by peptidases and other enzymes. Modifications of native peptides that were followed are.
Backbone N-alkylation, Backbone C-alkylation, D-Amino acid/proline substitution, peptide bond isostere, cyclic aminoacids, dehydro amino acidsand β-alkylation. Peptidomimetics are usually designed based on analogy to the native peptide structure, then optimized to give the best possible pharmacokinetic properties.The forefront of the field is the rational design of peptidomimetics using computer modeling, database searching, combinatorial chemistry and screening approaches, and analysis of X-ray structure data.