Synthetic Approaches towards Peptidomimetic Design

The first steps in developing a lead peptidomimetic compound starting from a bioactive peptide are connected to comprehension of the key residues of the parent peptide for bioactivity, and also of potential weak sites for guiding the rational design of chemical modifications to improve enzymatic stability. The most conservative approach to dealing with modifications of the peptide is the introduction of local structural changes. The introduction of local modifications around side-chains is aimed mainly at modulating the conformational profile of the peptide, thus intervening on all the rotatable bonds present in the amino acid unit. Special interest in the development of peptidomimetic compounds has been oriented towards the generation of novel amino acid structures and of molecular scaffolds acting as dipeptide isosteres. Peptidomimetics are basically developed according to rational design or random screening.