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Peptidomimetics
Definition: peptidomimetics are small protein like chains which are designed to mimic a
peptide. They typically arise either from modification of an existing peptide, or by designing
similar systems that mimic peptides, such as peptiods & β- peptides.

Introduction
Peptide derivatives are the result of modifications of the original sequence in various degrees,
and a classification based on the importance of the chemical modifications, from conservative to
drastic, has been proposed accordingly .
Modified peptides: these molecules contain relatively small modifications that do not modify the
peptide bond, and thus they still possess a chemical structure of peptide nature.
Pseudopeptides: in these compounds partial modifications of either peptide bonds or side-chains
are introduced, contributing to the generation of molecules possessing a
chemical structure of only partial peptide nature.
•Peptidomimetics: these compounds do not possess any amide bond of the original peptide, and
the structural resemblance is related to the pharmacophore and to the pharmacological activity of
the bioactive peptide conformation.

Peptidomimetics need for drug potency

Disadvantages of peptides as drugs Advantages of peptidomimetics as drugs

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R1 O R3

H OH R3
N
N N N
H H HN
N
O R2 O 1. H
O
R2
Limited stability towards proteolysis by peptidases in O

gastrointestinal tract and in serum 1 .conformationally restricted structures can minimize

2.Poor transport properties from intestines to blood and binding to non target receptors and enhance the activity
across blood brain barrier due to high molecular weight at desired receptor.
and lack of specific transport systems 2.Addition of hydrophobic residues and or replacement
3.Rapid excretion through liver or kidneys of amide bonds results in better transport proteins
4.Inherent flexibility enables interaction with through cellular membranes.
multiple receptors besides target and could result in 3.Isosters, retro-inverso peptides,cyclic peptides and
undesired side effects. non-peptidomimetics all reduce rate of degradation by
peptidases and other enzymes.

Classification

The various types of peptidomimetics have been classified as below:

Type-I peptidomimetics or pseudopeptides:

These are synthesized by structure based drug design. These peptidomimetics are closely similar
to peptide backbone while retaining functional groups that makes important contacts with
binding sites of the receptors. Some units mimic short portions of secondary structure of peptide
for example p-turns and have been used to generate lead compounds. Many early protease
inhibitors were designed from substrate/product mimetics of the peptide bond in a transition state
or product state for the enzyme-catalyzed reaction. For example Pyrrolinones contains peptide-
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like side-chains that fit the active sites of most peptidases and also these are resistant to normal
proteolysis because they replace amide bonds with metabolically stable units on amino acid unit
of parent peptides

Type-II: peptidomimetics or functional mimetics:

These peptidomimetics are synthesized by molecular modeling and high throughput screening
(HTS) etc. These are small non-peptide molecule that binds to a peptide receptor. Morphine was
the first well-characterized example of this type of peptidomimetic. Initially, type I1 mimetics
were considered to be direct structural analogs of the natural peptide, but characterization of both
the endogenous peptide and antagonist's binding sites by site-directed mutagenesis indicate that
antagonists for a large number of receptors seem to bind to receptor subsites different than those
used by the parent peptide. Consequently, functional mimetics may not mimic the structure of
the parent peptide. Despite this uncertainty, the approach has been quite successful and produced
a number of potential drug lead structures. For example G-protein coupled receptor (GPCR)
antagonists.

Type-III peptidomimetics or topographical mimetics: These are synthesized by structure

based drug design which represents that they possess novel templates, which appear unrelated to
the original peptides but contain the essential groups, positioned on a novel non-peptide scaffold
to serve as topographical mimetics. Several type III peptidomimetic protease inhibitors have
been characterized where direct X-ray structural determination of both the peptide-derived
inhibitor and the heterocyclic non-peptide inhibitor complexes have been compared. These
examples demonstrate that alternate scaffolds can display side-chains so that they interact with
proteins in fashion closely related to that of the parent peptide for example non-peptide protease
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inhibitors.

Type-IV peptidomimetics or non-peptide mimetics: These are synthesized by Group

Replacement Assisted Binding (GRAB) technique of drug design. These structures might share
structural functional features of type I peptidomimetics, but they bind to an enzyme form not
accessible with type I peptidomimetics for example piperidine inhibitors.
Incorporating conformational constraints locally or globally

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Limitation of torsional angles available to active site peptide residues

 Sequentially substitute D-amino acids and conformationally constrained
amino acids for the natural residues in target.
 Conformationally restricted amino acids must retain the crucial side chain
interactions with the receptor.
 Constrained amino acids can be categorized by the torsional angles that they
restrict in the peptide.

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Conformational constraints:-

 Peptide derivatives that contain conformationally restricting amino acid units or other
conformational constraints called conformational constained(or restricted) peptide
analogs.
 Conformational restriction is a very powerful method for probing the bioactive
conformations of peptides.
 Small peptides have many flexible torsion angles so that enormous numbers of
conformations are possible in a solution
Methods for restricting-conformations
 Peptide back bone cyclization
 Disulfide bond formation
 Side-chain cyclization
 Metal ion chelation

For reducing the number of accessible conformations and rendering the

selectivity of synthetic peptides more stringent than that afford by the sequence
could take advantage by introduction of two main constaints in to peptide.

Two main methods are used

I .Global constraints
II .Local constraints

Global Restrictions through Cyclic Peptidomimetics

 The generation of cyclic peptidomimetics is very attractive in terms of constraining a

native peptide structure into a conformationally-reduced molecule.

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 This approach is different from the introduction of cyclic scaffolds, as it does not modify
the parent peptide locally but involves modification of the overall conformational profile
of the target peptide compound.
 The macrocyclic peptide has several advantages in improving the quality of the bioactive
compound in terms of bioavailability and potency, as the high proportion of cis amide
bonds and the absence of free C- and N-termini confer higher metabolic resistance,In
addition, the limited conformational freedom results in higher receptor selectivity and
binding affinity, by reducing unfavourable entropic effects.

The cyclization strategies can be classified with respect to backbone and side-chains as the
chemical moieties used to introduce the constraint .Cyclization between backbone elements is

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approached in several ways:

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• by tethering two amide nitrogen atoms with a linker (backbone to backbone);

• by introducing a chemical junction between a Cα and a nitrogen atom (backbone to

backbone);

• by linking an N-terminal amino group with an amide nitrogen atom with a spacer (head

to backbone);

• by cyclizing the two N- and C-terminal ends of a peptidomimetic structure with an amide bond
(head- to-tail).

Peptidomimetic Scaffolds

 A peptidomimetic compound is thought of as a small molecule mimicking the biological

activity of a peptide although being no longer a peptide in chemical nature
 . Generally,peptidomimetic molecules do not contain any peptide bonds and possess a
modular structure deriving from amino acids, carbohydrates or other types of building
blocks.
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 The ideal peptidomimetic molecules are developed with the aim of possessing
favourable PK properties for oral administration, and with improved stability and
specificity with respect to the parent bioactive peptide.
 Peptidomimetics are basically developed according to rational design or random screen-
ing. The first route generally follows a hierarchical approach as discussed above, together
with structural information about the target or conformational models of the parent
peptide to ascertain the rationale for molecular recognition.
 The most successful route, however, combines both approaches, starting from the ran-
dom screening of wide arrays of small molecule mimetics of the parent bioactive
peptide,followed by structural elaboration of hit compounds according to a rational
approach based on available structural data.
 A remarkable example of such a combined approach has been reported for the
development of peptidomimetic ligands of the bradykinin receptor.
Local restrictions
 The simplest local constraints in which introducing substitution of methyl group
for a hydrogen adjacent to a rotable bond.
 the streaic bulk of methyl group reduced the rotational freedom of two peptide
backbone angles .
 the introduction of an alkyl group either at ß-position or on aromatic ring of
naturally occurring aminoacids rigidifies conformational flexibility of side chain.
 three of natural amino acids show ß-disubstitutions
 Valine[two methyl groups]
 Isoleucine[methyl and ethyl]
 Threonine[methyl hydroxyl]
 Additionally,ß-substitution leads to second asymmetric centre in amino acid
structure.
 In allowing peptide backbone and side chain some degree flexibility.Another
advantage of these modifications is that extra alkyl groups can enhance
lipophilicity of peptide and therefore can help it to overcome membrane barrier.

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 Introduction of covalent bond between aromatic ring of α-aminoacid residue and
peptide backbone has proven to be a useful further conformation restriction.
 The most conservative approach to dealing with modifications of the peptide is
the introduction of local structural changes.
 These modifications are restricted to single amino acids and, thus, are local
alterations of the peptide structure, and can be grouped into side-chain and
backbone modifications, with the aim of introducing conformational restrictions
and to stabilize the molecule towards protease-mediated degradation.
 Extensive work has been undertaken with the aim of replacing peptide bonds with
suitable moieties, to improve the resistance of the peptide; such modification of
the peptide backbone generally refers to the isosteric or isoelectronic exchange of
units in the peptide chain, and to the introduction of additional fragments.
 This goal is generally achieved by single amino acid modifications or by
introducing dipeptide analogues.
 Both approaches are conceived to constrain the backbone rotational freedom,
resulting in an organized conformation that may also resemble secondary
structure, such as helices or turns, or to limit the rotational freedom of side-chains
and to allow for the topological orientation required by the pharmacophore.
 Modifications at every part of a single amino acid have been reported .
Specifically,
 (i)The amino group can be replaced with isosteric atoms or groups, such as oxygen,
keto-methylene or N-hydroxyl moieties
 (ii) the alpha carbon with nitrogen atoms, C-alkyl to achieve quaternary amino acids,
or boron atoms

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 (iii) The carbonyl group has been replaced with thiol, methylene, phosphinic group.

 Retro inverso peptides have been also proposed, which consist of an amino acid
moiety in which the relative positions of the original amino and carboxylic groups
have been reversed.

 As backbone modification is mainly addressed by introducing amide bond

surrogates with the aim of improving the stability of the peptide in vivo, several
amide bond isosteres have been proposed that mimic the structural features of the
peptide bond and in some circumstances modify the conformational profile and the
hydrogen-bonding capability, too

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 For example, the introduction of aliphatic moieties augments the conformational

flexibility locally, whereas the application of olefin isosteres does not alter such
topology.
 Moreover, the hydrogen-bonding capabilities are modulated by applying diverse
amide bond isosteres, such as sulfonamide, phosphinic or peptoids, depending on the
accessibility of donors or acceptors for such interactions
 The introduction of local modifications around side-chains is aimed mainly at
modulating the conformational profile of the peptide, thus intervening on all the
rotatable bonds present in the amino acid unit.
 Accordingly, several tethering approaches have been proposed to restrict the
conformational freedom of selected dihedrals .

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 Moreover, side-chain modifications have been introduced to explore pharmacophoric

steric and electronic interactions, such as modulation of the hydrophobic content by
adding aromatic moieties or the introduction of polar appendages to address any polar
or hydrogen-bonding interactions with the target receptor.
1 Single Amino Acid Modifications
 The approach of modifying a single amino acid unit within a peptide sequence is
generally
 achieved by introducing constraining elements so as to reduce the conformational
flexibility.
 Backbone alkylation causes the angles ϕ, ψ, χ to be constrained, and N-alkylation
 facilitates cis/trans amide bond isomerism, whereas in the backbone Cα-alkylation ϕ,
ψ are constrained to a helical or extended linear structure
1.1. Nα-Cα cyclized amino acids
The amino acids belonging to this class are generally considered as prolinemimetics, which
is unique among proteinogenic amino acids in having a cyclic nature and possessing
thecapability of giving cis/trans isomerization due to a reduced energetic barrier of
interconversion(about 2 kcal mol–1).

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Proline mimetics
• The presence of a bond connecting Nα to Cα that forms a cycle responsible for the reduced
conformational freedom around this amino acid;
• Rotation around the Cα–C=O bond is partially impaired for the nonbonded interaction between
the carbonyl group and the ring;
• The steric hindrance between the proline mimetic and vicinal residues affects the overall
conformation around this peptide sequence Specifically, proline and all the corresponding
peptidomimetics are able to constrain the conformational freedom related to the torsional angle
ϕ; some approaches generally followed are:
• Modulation of the ring size, ranging from aziridines to omoproline;
• Inclusion of heteroatoms, such as azaproline or silaproline;
• Introduction of substituents at positions 3, 4, 5 to improve the conformational restriction.

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1.2 Constraining the side-chain rational freedom.
The inclusion of rigidifying elements in amino acids and peptidomimetics with the aim of
reducing the conformational freedom of side-chains may be addressed by taking advantage
of double bonds or cycles . The application of α,β-unsaturated α-amino acids,also called
dehydro-amino acids, allows blocking the Cα-Cβ rotation, as defined by the χangle, and selecting
of an (E) or (Z) isomer depending on the desired position of the R side chain.
The conformational result for dehydro-amino acids, or by developing bicyclic α-amino acids to
embed such a bond within a ring, for phenylalanine. Major attention
has been directed toward the incorporation of conformationally restricted Phe and Tyr analogues
in δ-opioid receptor tetrapeptide agonists, as these amino acids are critical for opioid receptor
binding

2 Dipeptide Isosteres
Special interest in the development of peptidomimetic compounds has been oriented towards the
generation of novel amino acid structures and of molecular scaffolds acting as dipeptide isosteres
. This approach found many applications that aim to improve the stability of peptidomimetics
towards proteolysis by replacing the amide moiety with alternative molecular fragments often
embedded within cyclic structures. Moreover, the scaffold approach in generating dipeptide

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isosteres resulted in a remarkable strategy to constrain the conformational freedom of a specific
region of a peptide compound by blocking ϕ, ψ or ω rotations around backbone covalent bonds.
Dipeptide lactams are useful for potency enhancement, greater receptor selectivity, insight into
the biologically active conformation of the parent peptide and in increasing the stability
towards protease degradation.

Molecular scaffolds developed as constrained dipeptide isosteres

3.Retro-inverso Peptides

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A common approach for improving the resistance of a peptide compound towards protease
degradation is to develop a peptidomimetic structure possessing chemical modifications around
amide bonds that are subjected to hydrolysis. Retro-inverso isomerization is a method for
modifying the structure of the backbone so as to prevent the protease recognizing the peptide-
based inhibitor as a substrate. This can be achieved by replacing one or more l-amino acids with
the parent enantiomer, and at the same time inverting the backbone direction fromN→C toC→N.
The retro-inverso modification does not lead to a more constrained polypeptide, but rather the
major advantage over the corresponding peptide lies in
the higher in vivo stability due to the modification of amide bonds, which are recognized by
proteases for their hydrolysis. This approach is well-represented by the retro-inverso
peptidomimetic of the key tetrapeptide sequence found in gastrin

4.N-Methylation of Peptides
The improvement of oral bioavailability by multiple N-methylation is a significant advance
toward the development of peptide based therapeutics, which has hampered over the years due to
poor pharmacokinetic properties.

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Multiple N-methylation resulted in enhancement in the activity and selectivity of receptor
subtypes using either library or designed approaches and help in understanding finer details of
the bioactive conformation.
5 Azapeptides
Azapeptides are an interesting and synthetically easy to approach class of peptidomimetics
in which the Cα atom of the backbone is replaced isoelectronically by a nitrogen atom.
Azapeptides can be synthesized very easily from substituted hydrazines or hydrazides , such as
through the acylation of hydrazines and the incorporation of aza-amino acid esters into a peptide
chain. They have been shown to be therapeutically relevant, such as in the case of serine and
cysteine proteases inhibitors.

6 Peptoids
Peptoids can be described as mimetics of α-peptides in which the side chain is attached to the
backbone amide nitrogen instead of the α-carbon . This modification results in the formal shift of
the position of the side chain with respect to the parent peptide backbone.

Therapeutic uses of peptidomimetics:

 Anti-microbial activity
 Anti-cancer activity.
 Anti-viral activity.
 Anti-malarial activity.
 Immunosuppressant activity.
 Aminopeptidase N inhibition activity.

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 Motilin antagonistic activity.
 Analgesic activity.
Conclusion
 Continued development of conformational constraints that can provide new peptide and
peptidomimetic motifs for design.
 Continued development of topographical constraints, especially in conjunction with
conformational constraints, will provide new ways of evaluating peptide ligand receptor
or acceptor interactions.
 Contunied development of methods of stabilize peptides against proteolyte degradation
and to improve biodistribution.
 Further development of new and more robust methods for peptide and peptidomimetic
delivery and biodistibution.
 Further development of assay methods, especially methods for evaluating peptide ligands
in disease and pathological states as a part of ligand design.
 Further development of synthetic methods for synthesis of large peptides and proteins
that will allow for more widespread use of novel amino acid residues to explore protein
function.
 Continued development of peptide, peptoid and PNA analogs and derivatives that cross
membrane barriers, target intercellular receptor or acceptors, and enhace bioavailability.
 Development of large variety of peptide and peptidomimetics based conjugates for a
variety of uses in diagnosis, drug delivery and treatment of diseases.
 Continuned investigation of novel scaffolds that can mimic peptide secondary
structures[ѱ and ф space], such as α-helices,β-turns, β-sheets peptide topographical
structures and most challenging, that can mimic protein conformational changes such as
α-helix to β-sheet transctions.
 Continued development of cpmputational methods for evaluation of the conformational
and dynamic properties of peptides more quickly and more accurately.
REFERENCES :
PEPTIDOMIMETICS IN ORGANIC AND MEDICINAL CHEMISTRY BY ANDREA TRABOCCHI AND ANTONIA

GUARNA
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MEDICINAL CHEMISTRY & DRUG DISCOVERY BY BURGER SIXTH EDITION
https://www.slideshare.net/argautam786/global-and-local-restrictions-peptidomimetics.
https://www.google.com/search?
q=therapeutic+values+of+peptidomimetics&oq=therapeutic+values&aqs=chrome.2.69i57j0l5.28
830j0j7&sourceid=chrome&ie=UTF-8
https://dochot.net/philosophy-of-money.html?utm_source=smnr-2000-2001-peterson-
gretchen-pdf

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