A peptidomimetic is a small protein-like chain designed to mimic a
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. ...
. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as
peptoid
Peptoids (root from the Greek πεπτός, ''peptós'' "digested"; derived from πέσσειν, ''péssein'' "to digest" and the Greek-derived suffix -oid meaning "like, like that of, thing like a ______," ), or poly-''N''-substituted glycines, a ...
s and
β-peptides. Irrespective of the approach, the altered chemical structure is designed to advantageously adjust the molecular properties such as stability or
biological activity
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
. This can have a role in the development of drug-like compounds from existing peptides. Peptidomimetics can be prepared by cyclization of linear peptides or coupling of stable unnatural amino acids. These modifications involve changes to the peptide that will not occur naturally (such as altered backbones and the incorporation of nonnatural
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 ...
s). Unnatural amino acids can be generated from their native analogs via modifications such as amine alkylation, side chain substitution, structural bond extension cyclization, and isosteric replacements within the amino acid backbone.
Based on their similarity with the precursor peptide, peptidomimetics can be grouped into four classes (A – D) where A features the most and D the least similarities. Classes A and B involve peptide-like scaffolds, while classes C and D include small molecules (Figure 1).
Uses of Peptidomimetics
The use of peptides as drugs has some disadvantages because of their bioavailability and biostability. Rapid degradation, poor oral availability, difficult transportation through cell membranes, nonselective receptor binding, and challenging multistep preparation are the major limitations of peptides as active pharmaceutical ingredients.
Therefore, small protein-like chains called peptidomimetics could be designed and used to mimic native analogs and conceivably exhibit better pharmacological properties.
Many peptidomimetics are utilized as FDA-approved drugs, such as
Romidepsin (Istodax),
Atazanavir (Reyataz),
Saquinavir (Invirase),
Oktreotid (Sandostatin),
Lanreotide (Somatuline),
Plecanatide
Plecanatide, sold under the brand name Trulance, is a medication for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases i ...
(Trulance),
Ximelagatran
Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin thera ...
(Exanta),
Etelcalcetide
Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelc ...
(Parsabiv), and
Bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
(Velcade).
D-peptides
A D-
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. ...
is a small sequence of
D-amino acids
D-Amino acids are amino acids where the stereogenic carbon alpha to the amino group has the D-configuration. For most naturally-occurring amino acids, this carbon has the L-configuration. D-Amino acids are occasionally found in nature as residu ...
. 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 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 to fold, its D-
enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
protein should have a mirror image conformation with respect to the L-protein (Figure 2). 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 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
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
. 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 response.
Methods to designing D-peptides
Ret design
An L-peptide has three analogue sequences (Figure 3) 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, consisting 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 is a laboratory technique for the study of protein–protein, protein–peptide, and protein– DNA interactions that uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes ...
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 fused to the gene of the protein coat of
bacteriophage
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bac ...
s and introduced into a vector. Diversity can be introduced to the peptide by
mutagenesis. 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. 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.
Structural similarity
Peptide with secondary structure cannot be mimicked by its retro-inverse, as linking in the reverse order breaks many backbone interactions essential for the secondary structure. An approach to mimicking these peptides is by searching for similar (sidechain) structures in a mirrored copy of the
Protein Data Bank
The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, cr ...
for the structured elements, and then linking the sections by retro-inversed versions of the loops found in the original protein.
Small molecules
Examples
Peptidomimetic approaches have been utilized to design small molecules that selectively kill cancer cells, an approach known as
targeted chemotherapy, by inducing programmed cell death by a process called
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
. The following two examples mimic proteins involved in key
Protein–protein interactions that reactivate the apoptotic pathway in cancer but do so by distinct mechanisms.
In 2004, Walensky and co-workers reported a stabilized
alpha helical peptide that mimics pro-apoptotic BH3-only proteins, such as
BID and
BAD.
This molecule was designed to stabilize the native helical structure by forming a
macrocycle between side chains that are ''not'' involved in binding. This process, referred to as
peptide stapling, uses
non-natural amino acids to facilitate macrocyclization by
ring-closing olefin metathesis. In this case, a stapled BH3 helix was identified which specifically activates the mitochondrial apoptotic pathway by
antagonizing the sequestration of BH3-only proteins by anti-apoptotic proteins (e.g.
Bcl-2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
, see also
intrinsic and extrinsic inducers of the apoptosis). This molecule suppressed growth of human
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
in a mouse
xenograft
Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograf ...
model.
Also in 2004,
Harran
Harran (), historically known as Carrhae ( el, Kάρραι, Kárrhai), is a rural town and district of the Şanlıurfa Province in southeastern Turkey, approximately 40 kilometres (25 miles) southeast of Urfa and 20 kilometers from the border ...
and co-workers reported a
dimeric small molecule that mimics the proapoptotic protein Smac (see
mitochondrial regulation in apoptosis). This molecule mimics the N-terminal
linear motif Ala-Val-Pro-Ile. Uniquely, the dimeric structure of this peptidomimetic led to a marked increase in activity over an analogous monomer. This binding
cooperativity
Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting indepen ...
results from the molecule's ability to also mimic the homodimeric structure of Smac, which is functionally important for reactivating caspases. Smac mimetics of this type can sensitize an array of
non-small-cell lung cancer cells to conventional chemotherapeutics (e.g.
Gemcitabine
Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...
,
Vinorelbine) both in vitro and in mouse xenograft models.
Heterocycles are often used to mimic the amide bond of peptides. Thiazoles, for example, are found in naturally occurring peptides and used by researchers to mimic the amide bond of peptide.
See also
*
Apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
*
Beta-peptide
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 c ...
*
Cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
*
Clicked peptide polymer
*
Depsipeptide A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR, Many depsipeptides have both peptide and ester linkages. Elimination of the N–H group in a peptide structure results ...
*
Expanded genetic code
*
Foldamers
*
Non-proteinogenic amino acids
References
Further reading
*
{{refend
Molecular biology
Organic chemistry