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

amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

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 ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...

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) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...

. 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 th ...

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 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.

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. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

s, β-peptides form disparate

secondary structure Protein secondary structure is the three dimensional form of ''local segments'' of proteins. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary struct ...

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 is derived from a cycloal ...

substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''sid ...

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

gauche conformation In chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted just by rotations about formally single bonds (refer to figure on single bond rotation). While any two arrangements of atoms in a mole ...

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

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

and in vivo, 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 agains ...

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

α-amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...

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, also called vitamin B5 is a water-soluble B vitamin and therefore an essential nutrient. All animals require pantothenic acid in order to synthesize coenzyme A (CoA) – essential for fatty acid metabolism – as well as to, i ...

, 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. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

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 toxins produced by certain freshwater cyanobacteria, commonly known as blue-green algae. Over 250 different microcystins have been discovered so far, of which microcystin-LR is the most common. Che ...

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

References