The document discusses modification of the peptide backbone and incorporating conformational constraints locally or globally to develop peptidomimetics. Peptidomimetics are designed to overcome stability issues with natural peptides and improve pharmacological properties. The peptide backbone can be modified through isoelectric or isoelectronic substitution or replacing the peptide bond with other chemical groups. Conformational constraints can be introduced globally through cyclization or locally by adding methyl groups or other alkyl substitutions to restrict backbone torsion angles. These modifications help reduce the number of accessible peptide conformations and increase selectivity, stability, and oral bioavailability.

1. MODIFICATION OF THE PEPTIDE
BACKBONE, ICORPORATING
COFORMATIONAL CONSTRAINTS
LOCALLY OR GLOBALLY
Presenting by ,
Mr Purushotham KN
Asst.Professor
Department of
Ph.Chemistry.
SACCP,B.G.Nagara
2021-2022
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2. Contents
 Introduction
 Modification of the Peptide backbone
 Incorporating conformational constraints locally or globally
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3. Introduction
 Peptidomimetics are compounds whose essential elements
(pharmacophore) mimic natural peptide or protein in a 3D space
and which upon modification, retain the ability to interact with the
biological target and produce the same biological effect as that of
the natural protein or peptide.
 And these peptidomimetics binds to enzymes/receptors with the
higher affinity than the previous peptide. And overall it leads either
increase(agonist) or decrease(inhibition) in the activity.
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4. •Apart from being much more selective, efficient and lowered
enzymatic degradation than native peptides, they also results I
fewer side effects.
•Peptidomimetics are mainly designed to overcome some of the
problems associated with natural peptides and proteins such as
stability problems and poor oral bioavailability, receptor
selectivity and potency issue.
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5. MODIFICATION OF PEPTIDE BACKBONE
The backbone of isoelectric and isoelectronic substitution.
Various peptidomimetics or peptide bond surrogates, in which peptide
bonds have been replaced with other chemical groups, are designed and
synthesized with the aim to obtain peptide analogs with improved
pharmacological properties.
This is mainly because such approaches create an amide bond surrogate
with defined 3 dimensional structures and with significant differences in
polarity, hydrogen bonding capability and acid-base character.
Also important, the structural and stereochemical integrities of the
adjacent pair of alpha carbon atoms in these pseudo peptides are unchanged.
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6. INCORPORATING CONFORMATIONAL CONSTRAINTS
LOCALLY OR GLOBALLY
Peptide derivatives that contain conformationally restricting amino acid
units or other conformational constraints called conformationally
constrained (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 solution.
Fig. Backbone and side chain torsional angles.
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7. •For example, a simple tripeptide such as thyrotropin-releasing
hormone with six flexible bonds could have over 65,000 possible
conformations. The number of potential conformers for larger
peptides is enormous.
Thyrotropin-releasing hormone
NH
NH2
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8. Methodologies for design peptides
for reducing the number of the 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 constraints in to peptide
Two main methods are used:-
local constraints
Global constraints
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9. Global restrictions
simplest way to introduce a conformational constraint into a
peptide sequence is by cyclization.
increases the in vivo stability of the cyclic peptides compared to
linar one.
Cyclization can be obtained by:
connecting the N- with the C-terminus (head-to-tail) portion of
the peptide sequence. or
Couple of either the N- or the C-terminus with one of the side
chains (backbone-to-side chain).
The couple of side chains not involved in specific interactions
with other (side chain-to-side chain).
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12. Local restrictions
•The simplest local constraints in which introducing the
substitution of a methyl group for a hydrogen adjacent to a
rotatable bond.
• For example, replacing the α-hydrogen on alanine with a
methyl group gives o – amino iso butyric acid (Aib). This residue
was found in peptide sequences from a fungal source.
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13. The steric bulk of the methyl group reduced the rotational
freedom of the two peptide backbone angles Ѱ and Ф.
In the case of Aib, the allowable Фand Ѱ backbone angles in
peptides are restricted to values near -57⁰, -47⁰ and +57⁰, +47⁰.
The introduction of an alkyl group either at the β-position or on
aromatic ring of naturally occurring amino acids rigidifies the
conformational flexibilities of the side chain.
CH3
O
O
H
C
H3
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14. •Three of natural amino acids show β - disubstitutions :
•Valine (two methyl groups)
•Isoleucine (a methyl and an ethyl) and
•Threonine (a methyl and a hydroxyl).
Additionally, b-substitution leads to a second asymmetric center
in the amino acid structure.
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15.  It allowing the peptide backbone and the side chain some degree
flexibility.
Another advantage of these modifications is that the extra alkyl
groups can enhance the liphophilicity of peptide, and therefore can
help it overcome membrane barrier.
The introduction of a Covalent bond between the of an α-amino
acid residue and the peptide backbone has proven to be a useful
further conformation restriction,
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17. References
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 Guarna A, Trabocchi A, Peptidomimetics in organic and
medicinal chemistry. John Wiley & sons;
Kharb R, Rana M, Sharma PC, Yar MS. Therapeutic
importance of peptidomimetics in medicinal chemistry.

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WHEN YOU STOP LEARNING…
YOU STOP GROWING.
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