Case histories of peptidomimetics: Progression from peptides to drugs†

There is a growing number of biologically active peptides which have potential for the development of new therapeutics. However, native peptides are only rarely directly usable as drugs, due to inherent limitations which include rapid proteolysis and metabolism, poor transport properties, rapid excretion by the liver and kidneys, and low oral activity. Furthermore, peptides are often aselective in their actions owing to their flexible structure. In efforts to address these limitations, peptides are modified into mimetics with specific physical, chemical and biological characteristics. These so-called peptidomimetics are derived from peptides by partly or completely removing the amide bonds while retaining essential amino acid side chains in a defined, spatial relationship. They can be developed in a rational design cycle which starts either from a lead compound obtained in a screening programme or from the parent peptide. In the latter approach, which is the focus of this overview, first the smallest, active sequence is found, and the significance of each amino acid for the biological activity is determined. In the following steps the bioactive conformation is defined by the introduction of local and global constraints. In the final step the essential amino acid side chains are positioned onto a scaffold, preferably a small, polyfunctional ring of defined stereochemistry, using structural information obtained in earlier steps. Five examples of the application of the peptidomimetic design cycle in medicinal chemistry are described here, illustrating the progression from native peptides to therapeutically useful drugs.