Beta-peptide

Beta-peptides (β-peptides) are peptides derived from β-amino acids, in which the amino group is attached to the β-carbon (i.e. the carbon two atoms away from the carboxylate group). The parent β-amino acid is β-alanine (H₂NCH₂CH₂CO₂H), a common natural substance, but most examples feature substituents in place of one or more C-H bonds. β-peptides usually do not occur in nature. β-Peptide-based antibiotics are being explored as ways of evading antibiotic resistance.^[1] Early studies in this field were published in 1996 by the group of Dieter Seebach^[1] and that of Samuel Gellman.^[2]

β-alanine, an example of a β-amino acid. The amino group attaches not to the α carbon but to the β-carbon, which in this case is a methylene group.

Structure

As there are two carbon atoms available for substitution, β-amino acids have four sites (chirality included; as opposed to two in α-amino acids) for attaching the organic residue group.^[3] Accordingly, two main types β-amino acids exist differing by which carbon the residue is attached to: ones with the organic residue (R) next to the amine are called β³ and those with position next to the carbonyl group are called β². A β-peptide can consist of only one kind of these amino acids (β²-peptides and β³-peptides), or have a combination of the two. Furthermore, a β-amino acid can form a ring using both of its sites and also be incorporated into a peptide.^[3]

Synthesis

β-Amino acids have been prepared by many routes,^[4][5] including some based on the Arndt-Eistert synthesis.

Secondary structure

Because their backbones are longer than those of normal peptides, β-peptides form disparate 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,^[6] and 10/12-helix have been reported. Generally speaking, β-peptides form a more stable helix than α-peptides.^[7]

Clinical potential

β-Peptides are stable against proteolytic degradation in vitro and in vivo, a potential advantage over natural peptides.^[8] β-Peptides have been used to mimic natural peptide-based antibiotics such as magainins, which are highly potent but difficult to use as drugs because they are degraded by proteolytic enzymes.^[9]

Examples

β-Amino acids with a wide variety of substituents exist. Named by analogy to the biological α-amino acids, the following have been found naturally: β-alanine, β-leucine, β-lysine, β-arginine, β-glutamate, β-glutamine, β-phenylalanine and β-tyrosine.^[10]: 23 Of these, β-alanine is found in mammals and incorporated in pantothenic acid, an essential nutrient.^[10]: 2 Two α-amino acids are also structurally β-amino acids: aspartic acid and asparagine.^[10]: 218 Microcystins are a class of compounds containing a β-isoaspartyl (i.e. aspartic acid linked with its beta-carboxyl) residue.^[10]: 23

See also

• Peptidomimetic