Beta-peptide

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]

Structure

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]

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

References

1. Seebach 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.
2. 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.
3. Seebach D, Matthews JL (1997). "β-Peptides: a surprise at every turn" (PDF). Chem. Commun. (21): 2015–22. doi:10.1039/a704933a.
4. 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. PMID   16292808.
5. 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. PMID   16173757.
6. Vasantha, Basavalingappa; George, Gijo; Raghothama, Srinivasarao; Balaram, Padmanabhan (January 2017). "Homooligomeric β3 (R)-valine peptides: Transformation between C14 and C12 helical structures induced by a guest Aib residue". Biopolymers. 108 (1): e22935. doi:10.1002/bip.22935. ISSN   1097-0282. PMID   27539268. S2CID   205497333. Archived from the original on 2022-02-13. Retrieved 2022-05-07.
7. Gademann K, Hintermann T, Schreiber JV (October 1999). "Beta-peptides: twisting and turning". Curr. Med. Chem. 6 (10): 905–25. doi:10.2174/092986730610220401154606. PMID   10519905. S2CID   247917035.
8. Beke T, Somlai C, Perczel A (January 2006). "Toward a rational design of β-peptide structures". J Comput Chem. 27 (1): 20–38. doi:10.1002/jcc.20299. PMID   16247761. S2CID   35579693.
9. Porter EA, Weisblum B, Gellman SH (2002). "Mimicry of host-defense peptides by unnatural oligomers: antimicrobial β-peptides". J. Am. Chem. Soc. 124 (25): 7324–30. doi:10.1021/ja0260871. PMID   12071741.
10. Juaristi, E.; Soloshonok, Vadim A. (6 May 2005). Enantioselective Synthesis of Beta-Amino Acids. Hoboken, New Jersey (NJ): Wiley Inc. ISBN   9780471698470. OCLC   559972352. Archived from the original on 7 May 2022. Retrieved 7 May 2022.