β-Peptides: a surprise at every turn

TLDR

β‑peptides, oligomers of β‑amino acids, can form exceptionally stable helices with central NH protons exchanging over days, and their greater structural variability yields a wide array of primary and secondary structures. The article reviews progress made since 1995 and discusses prospects for employing β‑peptides as drugs, building large enzymatically active β‑proteins, and interfacing with natural α‑peptidic systems. Enantiopure β‑amino acids are synthesized via homologation of α‑amino acids. β‑Peptides bearing side chains of common α‑amino acids are stable to peptidases for at least two days, and spectroscopic and crystallographic studies have revealed helical, pleated‑sheet and tubular arrangements in linear and cyclic β‑peptides up to twelve residues.

Abstract

β-Peptides, i.e. oligomers of β-amino acids, containing as few as six residues may form surprisingly stable helices, with half-lives for the H/D exchange of the central NH protons of up to several days. Furthermore, these β-peptides (carrying the side chains of familiar α-amino acids such as Ala, Val, Leu, Phe, Lys in the 2- and/or 3-position of their 3-amino carboxylic moieties) have been shown to be stable to common peptidases for at least two days. In this article, a brief account of the results obtained since we started work in this area in early 1995 is given. The synthesis of enantiopure β-amino acids can be achieved by homologation of α-amino acids. The greater structural variability of β-amino acids leads to an even greater multitude of possible β-peptide primary and secondary structures. Circular dichroism, NMR and X-ray investigations have unveiled helical, pleated-sheet and tubular arrangements of linear and cyclic β-peptides composed of up to twelve β-amino acids. The prospects for the use of β-peptides as drugs, the construction of large, enzymatically-active β-proteins and their interaction with the natural, α-peptidic counterparts are discussed.