CASE-HISTORIES OF PEPTIDOMIMETICS - PROGRESSION FROM PEPTIDES TO DRUGS

There is a growing number of biologically active peptides which have p otential for the development of new therapeutics. However, native pept ides are only rarely directly usable as drugs, due to inherent limitat ions which include rapid proteolysis and metabolism, poor transport pr operties, rapid excretion by the liver and kidneys, and low oral activ ity. 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 de rived from peptides by partly or completely removing the amide bonds w hile retaining essential amino acid side chains in a defined, spatial relationship. They can be developed in a rational design cycle which s tarts either from a lead compound obtained in a screening programme or from the parent peptide. In the latter approach, which is the focus o f this overview, first the smallest, active sequence is found, and the significance of each amino acid for the biological activity is determ ined. In the following steps the bioactive conformation is defined by the introduction of local and global constraints. In the final step th e essential amino acid side chains are positioned onto a scaffold, pre ferably a small, polyfunctional ring of defined stereochemistry, using structural information obtained in earlier steps. Five examples of th e application of the peptidomimetic design cycle in medicinal chemistr y are described here, illustrating the progression from native peptide s to therapeutically useful drugs.