Peptidomimetics

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.
An altered chemical structure is designed to adjust the molecular properties as, stability or biological activity.

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, B y designing similar systems that mimics peptides, such as P eptoids 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 Conformationally restrained structures can minimize binding to non-target receptors and enhance the activity at the desired receptor. Addition of hydrophobic residues and/or replacement of amide bonds results in better transport properties through cellular membranes. 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 Limited stability towards proteolysis by peptidases in the gastroeintesinal tract and in serum (t1/2 on the order of minutes) 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 Rapid excretion through the liver and/or kidneys 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 – 8 th 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 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. A new range of AMP(Antimicrobial peptides) termed “Peptidomimetics” were developed to mimic the bactericidal mechanism.