A peptidomimetic is a small protein-like chain designed to mimic a peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids
Peptoids, or poly-N-substituted glycines, are a class of peptidomimetics whose side chains are appended to the nitrogen atom of the peptide backbone, rather than to the α-carbons .-Chemical structure and synthesis:...

 and β-peptides
β-peptides consist of β amino acids, which have their amino group bonded to the β carbon rather than the α carbon as in the 20 standard biological amino acids. The only commonly naturally occurring β amino acid is β-alanine; although it is used as a component of larger bioactive molecules,...

. Irrespective of the approach, the altered chemical structure is designed to advantageously adjust the molecular properties such as, stability or biological activity. This can have a role in the development of drug-like compounds from existing peptides. These modifications involve changes to the peptide that will not occur naturally (such as altered backbones and the incorporation of nonnatural amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...


D-peptide peptidomimetics

A D-peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 is a small sequence of D-amino acids. Since ribosomes are specific to L-amino acids, D-peptides rarely occur naturally in organisms and are not easily digested or degraded. D-peptide peptidomimetics are D-peptides designed to mimic natural L-peptides that commonly have therapeutic properties.

Properties of D-peptides

When placed in a nonchiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 solvent like water, D-peptides, as well as the larger polypeptide D-proteins,
have similar but mirrored properties to the L-peptides and L-proteins
with identical sequences. If an L-protein does not require a Chaperone or a structural cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

 to fold, its
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

 protein should have a mirror image conformation with respect to the L-protein (Figure 1). A D-enzyme should act on substrates of reverse chirality compared to the L-enzyme with the same sequence. Similarly, if an L-peptide binds
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...

 to an L-protein, their D-peptide and D-protein counterparts
should bind together in a mirrored way.

D-peptides also have properties that make them attractive as drugs. D-peptides are less susceptible to be degraded in the stomach or inside cells by
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

. D-peptide drugs can therefore be taken orally and are effective for a longer period of time. D-peptides are
easy to synthesize, when compared to many other drugs. In some cases, D-peptides can have a low immunogenic
Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.- Immunogenicity :The ability to induce humoral and/or cell-mediated immune responses....


Ret design

An L-peptide has three analogue sequences (Figure 2) built from L and D amino acids: the D-enantiomer or inverso-peptide with the same sequence, but composed of D-amino
acids and a mirror conformation; the retro-peptide, consisting of the same sequence of L amino acids but in reverse order; and the
retro-inverso or D-retro-enantiomer peptide, consiting of D-amino acids in the reversed sequence.
While the L-peptide and its D-enantiomer are mirror structures of each other, the L-retro-peptide is the mirror image of the D-retro-inverso-peptide.
On the other hand, the L-peptide and the D-retro-inverso-peptide share a similar arrangement of side-chains, although their carboxyl and amino groups
point in opposing directions. For small peptides that do not depend on a secondary structure for binding, an L-peptide and its D-retro-inverso-peptide is likely to have
a similar binding affinity with a target L-protein.

Mirror-image phage display

Phage display
Phage display
Phage display is a method for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. Phage Display was originally invented by George P...

 is a technique to screen large libraries of peptides for binding to a target protein. In phage display,
the DNA sequence that codes the potential drug-peptide is fusioned to the gene of the protein coat of bacteriophages
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...

 and introduced into a
vector. Diversity can be introduced to the peptide by mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...

. The protein coats peptides are
then expressed and purified, and applied to a surface of immobilized protein targets. The surface is then washed away to remove non-binding
peptides, while the remaining binding peptides are eluted.
Mirror-image phage display is a similar method that can be used to screen large libraries of D-peptides that bind to target L-proteins. More precisely,
since D-peptides can not be expressed in bacteriophages, mirror-image phage display screens L-peptides that bind to immobilized D-proteins that are
previously chemically synthesized
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

. Because of the mirror properties of D-peptides, the D-enantiomer of an L-peptide that binds to a D-protein
will bind to the L-protein.

Mirror-image phage display, however, has two disadvantages when compared to phage display.
Target D-proteins must be chemically synthesized, which is normally an expensive and time consuming process. Also,
the target protein must not require a cofactor or a chaperone to fold, otherwise the chemically synthesized D-protein
will not fold to the target, mirror structure.


An example of peptidomimetics were those designed and synthesized with the purpose of binding to target proteins in order to induce cancer cells into a form of programmed cell death called apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. Basically, these work by mimicking key interactions that activate apoptotic pathway in the cell.

All healthy cells in metazoa (multi-celled animals) are subject to programmed cell death when they are no longer wanted; but cancer cells have the ability to evade apoptosis and the body's attempts to get rid of them. So peptidomimetics are part of the wide effort by researchers, research labs and institutions to create cures for cancer by means of restoring or activating apoptotic pathways in specific cells.

An impressive advance in this effort was reported by Loren D. Walensky and colleagues in the 3 September 2004 issue of the journal Science. This team succeeded in reducing a variety of human leukemic cells that had been xenografted (transplanted) into mice. The peptidomimetic that they succeeded in synthesizing, SAHB (stabilized alpha-helix of BCL-2 domains) specifically activates the mitochondrial apoptotic pathway in the aforementioned malignant cells (see intrinsic and extrinsic inducers of the apoptotic process), without harming healthy tissues.

Lin Li and co-workers reported another impressive advance in the same issue of Science. They were able to synthesize a molecule that mimics the proapoptotic protein called SMAC (whose function is described in biochemical execution of apoptosis).
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