Polyhydroxylated Cyclic Delta Amino Acids: Synthesis and Conformational Influences on Biopolymers

Abstract

This review is dedicated to the fitting and functional characterization of polyhydroxylated amino acids into protein environments, noting that systematic compendia of sugar-derived unnatural building blocks can be found in the literature. This review is focused on the local exchange of two sequential amino acids in a peptide or protein for a polyhydroxylated δ-amino acid in various applications ranging from ligand design to the investigation of protein function. Two general strategies are respectively differentiated that delete and retain the peptide backbone. So-called sugar amino acids (SAAs) exchange one peptide bond for a tetrahydropyran or furan ring. Alternatively, polyhydroxylated bicyclic dipeptides encompass an amide bond within their ring system and become integral parts of the peptide backbone (compare SAA and Xaa = Yaa in Fig. 1). In peptides, these polyhydroxylated ring systems may favor turn and loop conformations, modify polarity, and offer handles for ligation methods. The influence of ring substituents on these heterocycles is discussed with respect to their potential to increase the stability of particular conformations with preferred orientations as well as to mediate supramolecular interactions. In addition, examples of the use of polyhydroxylated ring systems to stabilize standalone peptide hairpins and mediate protein–protein interactions will be presented.