Beta-peptide
{{Short description|Class of peptides derived from β-amino acids}}
Image:Beta-alanineVSalpha-alanine.png.]]
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.{{cite journal |vauthors=Seebach D, Overhand M, ((Kühnle FNM)), Martinoni B, Oberer L, Hommel U, Widmer H |date=June 1996 |title=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 |journal=Helvetica Chimica Acta |volume=79 |issue=4 |pages=913–941 |doi=10.1002/hlca.19960790402}} Early studies in this field were published in 1996 by the group of Dieter Seebach and that of Samuel Gellman.{{cite journal|vauthors=Appella DH, Christianson LA, Karle IL, Powell DR, Gellman SH|year=1996|title=β-Peptide Foldamers: Robust Helix Formation in a New Family of -Amino Acid Oligomers|journal=J. Am. Chem. Soc.|volume=118|issue=51|pages=13071–2|doi=10.1021/ja963290l}}
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. 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.{{cite journal |vauthors=Seebach D, Matthews JL |title=β-Peptides: a surprise at every turn |journal=Chem. Commun. |issue=21 |pages=2015–22 |year=1997 |url=https://chab.ethz.ch/content/dam/ethz/special-interest/chab/chab-dept/department/images/Emeriti/Seebach/PDFs/596_CC_1997.pdf |doi=10.1039/a704933a }}
Synthesis
β-Amino acids have been prepared by many routes,{{cite journal |vauthors=Basler B, Schuster O, Bach T |title=Conformationally constrained β-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening |journal=J. Org. Chem. |volume=70 |issue=24 |pages=9798–808 |date=November 2005 |pmid=16292808 |doi=10.1021/jo0515226}}{{cite journal |vauthors=Murray JK, Farooqi B, Sadowsky JD |title=Efficient synthesis of a β-peptide combinatorial library with microwave irradiation |journal=J. Am. Chem. Soc. |volume=127 |issue=38 |pages=13271–80 |date=September 2005 |pmid=16173757 |doi=10.1021/ja052733v |display-authors=etal}} 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,{{Cite journal|last1=Vasantha|first1=Basavalingappa|last2=George|first2=Gijo|last3=Raghothama|first3=Srinivasarao|last4=Balaram|first4=Padmanabhan|date=January 2017|title=Homooligomeric β3 (R)-valine peptides: Transformation between C14 and C12 helical structures induced by a guest Aib residue|url=https://pubmed.ncbi.nlm.nih.gov/27539268|journal=Biopolymers|volume=108|issue=1|pages=e22935|doi=10.1002/bip.22935|issn=1097-0282|pmid=27539268|s2cid=205497333 |via=|access-date=2022-05-07|archive-date=2022-02-13|archive-url=https://web.archive.org/web/20220213154445/https://pubmed.ncbi.nlm.nih.gov/27539268/|url-status=live}} and 10/12-helix have been reported. Generally speaking, β-peptides form a more stable helix than α-peptides.{{cite journal |vauthors=Gademann K, Hintermann T, Schreiber JV |title=Beta-peptides: twisting and turning |journal=Curr. Med. Chem. |volume=6 |issue=10 |pages=905–25 |date=October 1999 |doi=10.2174/092986730610220401154606 |pmid=10519905 |s2cid=247917035 }}
Clinical potential
β-Peptides are stable against proteolytic degradation in vitro and in vivo, a potential advantage over natural peptides.{{cite journal |vauthors=Beke T, Somlai C, Perczel A |title=Toward a rational design of β-peptide structures |journal=J Comput Chem |volume=27 |issue=1 |pages=20–38 |date=January 2006 |pmid=16247761 |doi=10.1002/jcc.20299|s2cid=35579693 }} 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.{{cite journal |vauthors=Porter EA, Weisblum B, Gellman SH |title=Mimicry of host-defense peptides by unnatural oligomers: antimicrobial β-peptides |journal=J. Am. Chem. Soc. |volume=124 |issue=25 |pages=7324–30 |year=2002 |doi=10.1021/ja0260871 |pmid=12071741}}
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.{{cite book |last1=Juaristi |first1=E. |last2=Soloshonok |first2=Vadim A. |url=https://books.google.com/books?id=WpgRvHGa0zIC&dq=8%20beta%20forms&pg=PA23 |title=Enantioselective Synthesis of Beta-Amino Acids |date=6 May 2005 |publisher=Wiley Inc. |isbn=9780471698470 |location=Hoboken, New Jersey (NJ) |oclc=559972352 |access-date=7 May 2022 |archive-date=7 May 2022 |archive-url=https://web.archive.org/web/20220507184706/https://www.google.co.in/books/edition/Enantioselective_Synthesis_of_Beta_Amino/WpgRvHGa0zIC?hl=en&gbpv=1&dq=8+beta+forms&pg=PA23 |url-status=live }}{{rp|23}} Of these, β-alanine is found in mammals and incorporated in pantothenic acid, an essential nutrient.{{rp|2}} Two α-amino acids are also structurally β-amino acids: aspartic acid and asparagine.{{rp|218}} Microcystins are a class of compounds containing a β-isoaspartyl (i.e. aspartic acid linked with its beta-carboxyl) residue.{{rp|23}}