A journey from the pool of chiral synthetic building blocks to cell-penetrating peptides, to a novel type of enzyme -and back

Abstract

The roles of polyhydroxy-butyrates/alkanoates (PHB/PHA) in biology, for the preparation of chiral building blocks, and as a source of inspiration for the discovery of β- and ?-peptides are discussed. The syntheses and structures of β-peptides are outlined. The prerequisites for mimicking peptide/protein interactions with β-peptides and two examples are presented. Single terminal β-amino-acid residues can lead to stabilization of peptides (cf. NTS(8-13)) in plasma. Cell-penetrating α-l-, α-d-, mixed α-l/d- and β-oligoarginines (OAs) and -oligoprolines, as well as the mechanism(s) of internalization are compared. Recent studies show that infected erythrocytes, parasitic organisms and mycobacteria are entered by OA-derivatives, which have been employed as transporters of the antibiotic fosmidomycin. While β-peptides are generally enzymatically stable (for days in mammals), a microorganism (S. xenopeptidilytica) with an Ntn enzyme (3-2W4 BapA) was discovered that cleaves only β-peptides, and that was applied in preparations of (enantiopure) β-amino acids and β-peptides. © Schweizerische Chemische Gesellschaft.