Synthesis of Peptide Mimetics and their Building Blocks

Abstract

Very many peptides have the potential of being used as drugs. Nevertheless, they usually suffer from serious limitations stemming from their metabolic lability and unfavorable pharmacokinetics. A promising approach to circumvent these problems is the use of conformationally similar molecules, able to interact with the same biological targets, but less susceptible to metabolic degradation and with better absorption and distribution properties. This may be achieved through the synthesis of peptide mimetics where some or all of the amino acid residues have been replaced by different chemical moieties. This article gives a brief overview of peptide mimetic structures on which medicinal chemists have focused in the last few years, together with the chemical approaches used for their synthesis and of the amino acid replacements that serve as their building blocks. These methods range from classical organic synthetic methods to quite sophisticated catalytic and solid-phase protocols. In many cases, the target compounds have been tested in biological systems with varying degrees of success. These results should not be construed as an indication of unreliability of the peptidomimetic approach, but rather as a reflection of the limited sample examined to date. Because of the solid foundations on which this therapeutic strategy is based, we think that a growing number of peptide mimetics are likely to enter the clinic in the coming years. Keywords: Azapeptides; Aminooxy Peptides; Oligocarbamate; Oligourea; β-, γ-, δ-, ɛ-Peptides; Peptide Mimetics (or Peptidomimetics); Peptoids