β-Amino Acids: Versatile Peptidomimetics

Abstract

The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the physical characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of beta-amino acids. Beta-amino acids are similar to alpha-amino acids in that they contain an amino terminus and a carboxyl terminus. However, in beta-amino acids two carbon atoms separate these functional termini. beta-amino acids, with a specific side chain, can exist as the R or S isomers at either the alpha (C2) carbon or the beta (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of beta-amino acids thereby providing enormous scope for molecular design. The incorporation of beta-amino acids has been successful in creating peptidomimetics that not only have potent biological activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of beta-amino acids in the design of bioactive peptide analogues ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using standard solid-phase peptide synthesis techniques, beta-amino acids have the potential to form a new platform technology for peptidomimetic design and synthesis.