From the Biopolymer PHB to Biological Investigations of Unnatural β- and γ-Peptides

Abstract

An overview is given of the past and present activities of our group in the field of chemical biology. Thus, the polymer of 3-hydroxybutanoic acid (PHS), which is omnipresent in living organisms, triggered our search for a better analytical method for detecting PHB and our syntheses of oligomers of 3-hydroxyalkanoic acids (OHSs). Also, the regulation of DNA replication by poly(β-malic acid) (PMA) in certain eukaryotes inspired synthetic work on the corresponding cyclic and open-chain oligomers. With these oligomers we not only tested the mechanisms of depolymerases, but were able to study the properties and activities of well-characterized compounds (also with isotope and fluorescence labeling). The role of PHS as component of ion transport systems through phospholipid bilayers was unambiguously established, and models for the channel structure were proposed. Replacement of amino acids by 3-hydroxybutanoic acid residues in peptides and replacement of the chain-bound oxygens in OHB by NH paved our way into the world of β- and γ-peptides, the synthesis and physiological and pharmacological properties of which are being investigated. β-Peptides are stable to peptidases, have a long lifetime in mammalian serum and are rather resistant to environmental microbial degradation. The peptides consisting of homologated (β) or doubly homologated (γ) amino acids form stable secondary structures in solution (helices, turns, sheets) which can be used as scaffolds for peptide mimics, such as a β-tetrapeptide with affinity to a somatostatin receptor or a β-nonapeptide that inhibits intestinal lipid-transport protein (SR-BI) in Caco-2 cells. Certain β-peptides have antibacterial, antiproliferative and haemolytic properties. The lessons from studies of β- and γ-peptides teach us about the central role of natural α-peptidic proteins.