2.5 Natural β-amino Acids and β-peptides

Introduction

β-peptides consist of β amino acids, which have their amino group bonded to the β- carbon rather than the α-carbon as in the 20 standard biological amino acids. The only commonly naturally occurring β-amino acid is β-alanine which is used as a component of larger bioactive molecules. However, β-peptides in general do not appear in nature. For this reason β-peptide-based antibiotics are being explored as ways of evading antibiotic resistance. Studies in this field were explored first in 1996 by the group of Dieter Seebach and that of Samuel Gellman.

Figure 2.24: The chemical structures of naturally occurring and few unnatural β- amino acids.

The folded structures in natural polypeptides containing α-amino acids are conveniently defined using backbone torsion angles Φ and ψ. Each α-amino acid residue possesses two degrees of torsional freedom about the N−Cα (Φ) and Cα-CO (ψ) bonds, with the peptide bond restricted to a trans, planar (ω ≈ 180°) conformation. The Ramachandran map provides a convenient means of analyzing and representing the observed backbone conformations of α-amino acid residues in peptides and proteins. A very large numbers of natural and unnatural amino acids have been utilized to generate mimic many biologically and structurally interesting compounds peptides and proteins. Gellman and co-workers have studied several model peptides containing covalently constrained β-amino acids. Their study led to the realization that new classes of folded unnatural polypeptide structures could be generated. The insertion of additional atoms in between the flanking peptide units enhances the number of degrees of torsional freedom, resulting in an expansion of energetically accessible conformational space. As for example, in the β-amino acid residue, local backbone conformations are determined by values of three torsional variables (Φ, θ, and ψ) while for the γ-residue, the number of torsional variables is four (Φ, θ1, θ2, and ψ) (Figure 2.25).

Figure 2.25: Substitution patterns for a β-amino acid residue.

A poly-β-amino acid helix introduced by Kovac et al. in 1965 has 3.4 residues/turn and an axial translation of 1.58 Å/ residue. It is necessarily right-handed for the β-amino acids with the L-configuration at the α-carbon. Recent interest in the chemistry and biology of peptides containing backbone expanded amino acid residues stems from the studies reported in the mid 1990s that novel polypeptide helices could be formed in oligo β-peptides and the characterization of hybrid structures that demonstrated that the β-and γ-residues can be accommodated into canonical helical folds, with an expansion of the intramolecular hydrogen bonded rings.