Beta-peptides (β-peptides) are peptides derived from β-amino acids, in which the

amino In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

group is attached to the β-carbon (i.e. the carbon two atoms away from the

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...

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 Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resis ...

. Early studies in this field were published in 1996 by the group of

Dieter Seebach Dieter Seebach is a German chemist known for his synthesis of biopolymers and dendrimers, and for his contributions to stereochemistry. He was born on 31 October 1937 in Karlsruhe. He studied chemistry at the University of Karlsruhe (TH) under t ...

and that of Samuel Gellman.

Structure

As there are two carbons available for substitution, β-amino acids have four sites (chirality included; as opposed to two in

α-amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s) 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.

Synthesis

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

Secondary structure

Because their backbones are longer than those of normal

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s, β-peptides form disparate

secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

s. The

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...

substituent In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...

s at both the α and β positions in a β-amino acid favor a

gauche conformation In chemistry, rotamers are chemical species that differ from one another primarily due to rotations about one or more single bonds. Various arrangements of atoms in a molecule that differ by rotation about single bonds can also be referred to as ...

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.

Clinical potential

β-Peptides are stable against

proteolytic degradation Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

and

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

, a potential advantage over natural peptides. β-Peptides have been used to mimic natural peptide-based antibiotics such as

magainin The magainins are a class of antimicrobial peptides found in the African clawed frog (''Xenopus laevis''). The peptides are cationic, generally lack a stable conformation in water but form amphipathic α-helix in membranes; their mechanism agai ...

s, which are highly potent but difficult to use as drugs because they are degraded by proteolytic enzymes.

Examples

β-Amino acids with a wide variety of substituents exist. Named by analogy to the biological

s, the following have been found naturally: β-alanine, β-leucine, β-lysine, β-arginine, β-glutamate, β-glutamine, β-phenylalanine and β-tyrosine. Of these, β-alanine is found in mammals and incorporated in

pantothenic acid Pantothenic acid (vitamin B5) is a B vitamin and an essential nutrient. All animals need pantothenic acid in order to synthesize coenzyme A (CoA), which is essential for cellular energy production and for the synthesis and degradation of prote ...

, an essential nutrient. Two α-amino acids are also structurally β-amino acids:

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...

and

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

Microcystin Microcystins—or cyanoginosins—are a class of cyanotoxins, which are toxins produced by cyanobacteria, sometimes known as blue-green algae. Over 250 different microcystins have been discovered so far, of which microcystin-LR is the most commo ...

s are a class of compounds containing a β-isoaspartyl (i.e. aspartic acid linked with its beta-carboxyl) residue.

References