This document discusses peptidomimetics, which are small protein-like chains designed to mimic peptides while having no peptide bonds and a molecular weight under 700 Daltons. Peptidomimetics are derived from bioactive peptides and aim to improve stability, transport properties, and activity while reducing degradation. They are classified based on their modifications from the original peptide. Common modification methods include cyclization, retro-inverso design, and restricting conformations through disulfide bonds or metal chelation. Peptidomimetics have therapeutic value as they can overcome issues like poor oral bioavailability that limit peptide drugs, as demonstrated for somatostatin analogs. Recent advances include using peptidomimetics to enhance peptide vaccines

1. SAKEEL AHMED (PhD Scholar)
Department of Pharmacology (NIPER, Mohali)
PEPTIDOMIMETICS

2. Introduction
• Peptidomimetics are small protein – like chain designed to mimic a peptide, have no
peptide bonds and MW<700D
• Peptidomimetics are chemical structures derived from bioactive peptides
which imitate natural molecules.
• Arise either from –
 Modification of an existing peptide,
 By designing similar systems that mimics peptides, such as Peptoids and β-peptides.
• Altered chemical structure is designed to adjust the molecular properties as, stability
or biological activity.

3. Peptides act as
Neurotransmitter.
Neuromodulators.
Hormones.
Autocrine and Paracrine factors
Peptides have poor pharmacokinetic properties
Easily proteolyzed.
Poor transportation.
Rapid excretion.
To replace portions of peptides with non-peptide structures.
Peptide 2 is derived from the
decapeptide LH-RH 1 is completely
different from 1 yet is a powerful
antagonist to LR-RH receptor.

4. Classification
Class
A
• Modified peptides: peptides mainly formed by α-amino acids with
minor side chain or backbone alterations.
Class D
Non-Peptide peptidomimetics : GRAB peptidomimetic (Group
replacement assisted binding).
Class C
• Structural mimetics: small molecules-like scaffolds that project
substituents in analogy to peptide side chains.
Class
B
• Mechanistic mimetics: molecules that mimics the mode of action
of a peptides without direct link to its side chains.

5.  Advantages of Peptidomimetics as Drugs
1. Conformationally restrained structures can
minimize binding to non-target receptors
and enhance the activity at the desired
receptor.
2. Addition of hydrophobic residues and/or
replacement of amide bonds results in
better transport properties through cellular
membranes.
3. Isosteres, retro-inverso peptides, cyclic
peptides and non-peptidomimetics all
reduce the rate of degradation by
peptidases and other enzymes.
 Disadvantages of Peptides as Drugs
1. Limited stability towards proteolysis
by peptidases in the gastroeintesinal tract
and in serum (t1/2 on the order of minutes)
2. Poor transport properties from the
intestine to the blood and across the
blood-brain barrie due to high MW and
lack of specific transport systems
3. Rapid excretion through the liver and/or
kidneys
4. Inherent flexibility enables interaction with
multiple receptors besides the target, and
could result in undesired side-effects
Advantages and Disadvantages

6. Methods of modification

7. Cyclization
 One of the earliest techniques applied to design Peptidomimetics
 Cyclic peptides are more stable to amide bond hydrolysis.
 Allow less conformational flexibility
 Expected to be more selective and less toxic
Figure: Cyclization of alpha-
melanotropin gave the
unusually active analog
after cyclization.

8.  The reversal of the amide bond direction minimizes peptidase degradation,
thereby increasing the mimetics in vivo half-life.
 Inversion of each stereocentre from L to D preserve the 3-D orientation of the
side chain residue of the original peptide.
 Reversal of the Carboxy and amino terminal reverse the charge structure of
the peptide and may be the cause of their low biological activity.
 End group modifications increased the complementarity of the
peptidomimetics with the native peptides and has resulted in several potent
peptidomimetics.
Retro-Inverso Peptidomimetics
• Tuftsin is a immune system stimulator
which is completely degraded in vivo in
8 min.
• The retro-Inverso peptidomimetic
shows less than 2% hydrolysis after 50
min and retention of bioactivity.

9. Methods of restricting conformations
 Peptide backbone cyclization
 Disulfide bond formation
 Side-chain cyclization
 Metal ion chelation
First successful application – Veber et al at Merck –
Somatostatin – to get orally bioactive derivative
Rivier – 8th position L-Tryptophan by
D- Tryptophan produced an analog which retained
Biological activity.
This is possible at a type II’ beta turn – as topography of
aa sidechain is identical In these turns.
Tetrapeptide is the pharmacophore
1. deleted N-terminal dipeptide
2. Insert D-Try at 8
3. Replace disulfide sulfur with carbon produced analogs
(9)
Compound 11.
Retained only 6 of the
Original 14 aa in somatostatin yet
Produced a fully active derivative

10. Therapeutic Value of Peptidomimetics

11. Recent Advances In Peptidomimetics
i. Peptides vaccines were developed for the prevention and
treatment of pathogenicity diseases,cancer and autoimmune
disorders but because of low immunogenicity and reduced
bioavailability they have become unsuccessful peptidomimetics
were developed through chemical alteration of epitope structure
to overcome this side effects.
ii. A new range of AMP(Antimicrobial peptides) termed
“Peptidomimetics” were developed to mimic the bactericidal
mechanism.