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.
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]
As there are two carbons 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]
Because their backbones are longer than those of normal peptides, β-peptides form disparate secondary structures. The alkylsubstituents 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]
β-peptides are stable against proteolytic degradationin 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]
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
^ abSeebach D, Overhand M, Kühnle FNM, Martinoni B, Oberer L, Hommel U, Widmer H (June 1996). "β-Peptides: Synthesis by Arndt-Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X-ray crystallography. Helical secondary structure of a -hexapeptide in solution and its stability towards pepsin". Helvetica Chimica Acta. 79 (4): 913–941. doi:10.1002/hlca.19960790402.
^Appella DH, Christianson LA, Karle IL, Powell DR, Gellman SH (1996). "β-Peptide Foldamers: Robust Helix Formation in a New Family of -Amino Acid Oligomers". J. Am. Chem. Soc.118 (51): 13071–2. doi:10.1021/ja963290l.
^Basler B, Schuster O, Bach T (November 2005). "Conformationally constrained β-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening". J. Org. Chem. 70 (24): 9798–808. doi:10.1021/jo0515226. PMID16292808.
^Murray JK, Farooqi B, Sadowsky JD, et al. (September 2005). "Efficient synthesis of a β-peptide combinatorial library with microwave irradiation". J. Am. Chem. Soc. 127 (38): 13271–80. doi:10.1021/ja052733v. PMID16173757.
