Beta-peptide

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; although it is used as a component of larger bioactive molecules, 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. Pioneering studies in this field were published in 1996 by the group of Dieter Seebach and that of Gellman.

Chemical structure and synthesis

In α amino acids (molecule at left), both the carboxylic acid group (red) and the amino group (blue) are bonded to the same carbon, termed the α carbon (Cα) because it is one atom away from the carboxylate group. In β amino acids, the amino group is bonded to the β carbon (Cβ), which is found in most of the 20 standard amino acids. Only glycine lacks a β carbon, which means that there is no β-glycine molecule.

The chemical synthesis of β amino acids can be challenging, especially given the diversity of functional groups bonded to the β carbon and the necessity of maintaining chirality. In the alanine molecule shown, the β carbon is achiral; however, most larger amino acids have a chiral Cβ atom. A number of synthesis mechanisms have been introduced to efficiently form β amino acids and their derivatives notably those based on the Arndt-Eistert synthesis.

Two main types of β-peptides exist: those with the organic residue (R) next to the amine are called β³-peptides and those with position next to the carbonyl group are called β²-peptides.

Secondary Structure

Because the backbones of β-peptides are longer than those of peptides that consist of α-amino acids, β-peptides form different secondary structures. The alkyl substituents at both the α and β positions in a β amino acid favor a gauche conformation about the bond between the α-carbon and β-carbon. This also affects the thermodynamic stability of the structure.

Many types of helix structures consisting of β-peptides have been reported. These conformation types are distinguished by the number of atoms in the hydrogen-bonded ring that is formed in solution; 8-helix, 10-helix, 12-helix, 14-helix, and 10/12-helix have been reported. Generally speaking, β-peptides form a more stable helix than α-peptides.

The β-peptide zwit-1F with a fully described quaternary structure is called a β-protein because it has many characteristics of an actual protein. Eight 12-helix units self-assemble in water to a superstructure with a hydrophobic inner core.

Clinical potential

β-peptides are stable against proteolytic degradation in vitro and in vivo, an important advantage over natural peptides in the preparation of peptide-based drugs. β-peptides have been used to mimic natural peptide-based antibiotics such as magainins, which are extremely powerful but difficult to use as drugs because they are degraded by proteolytic enzymes in the body.