PEPTIDOMIMETICS [M.PHARM, BSC, MSC, B.PHARM]

PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS

1. PEPTIDOMIMETICS

2. Contents Introduction Classification Advantages and Disadvantages Method of preparation Peptidomimetics Drug Design Principle Chemistry and stereochemistry Synthesis Therapeutic value of peptidomimetics

3. Introduction A small protein – like chain designed to mimic a peptide , have no peptide bonds and MW<700D Arise either from – Modification of an existing peptide, or 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.

4. Defination Peptidomimetics are chemical structures derived from bioactive peptides which imitate natural molecules. A peptidomimetics is a small protein – like chain designed to mimic a peptide. They typically arise either from modification of an existing peptide, or by designing similar system that mimic peptides, such as peptoids and β-peptides .

5. Classification Chart No: 1

6. Advantages and Disadvantages 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

7. Methods of modification

8. Retro-Inverso Peptidomimetics

9. Morphine: a Non-peptidomimetics For Enkephaline

10. Somatostatine:Early Investigations

11. Peptidomimetic HIV-1 Protease Inhibitors

12. Peptidomimetics Drug Design Principle

13. Chemistry and Stereochemistry

14. Synthesis

15. Therapeutic Value of Peptidomimetics INNs Brand names Length Sequences Companies Indications Half-life Daptomycin Cubicin 13 aa N-Decanoyl-Trp-Asp-Asp- threonylglycyl-ornithyl-Asp-D-alanyl- aspartylglycyl-D-seryl-threo-3-methyl- glutamyl-3-anthraniloyl-alanine[egr]1- lactone Cubist Pharmaceuticals Antibiotic used to treat systemic and life- threatening infections caused by Gram-positive organisms 8–9 hours Afamelanotide Scenesse 13 aa Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg- Trp-Gly-Lys-Pro-Val-NH2 Clinuvel Pharmaceuticals Erythropoietic porphyries 100 min Eptifibatide Integrilin 7 aa c[Mpa-homoArg-Gly-Asp-Trp-Pro-Cys]- NH2 Millennium Pharms, GSK, Schering-Plough Acute coronary syndrome, unstable angina undergoing PCI 2.5 hours Cyclosporine Neoral, Gengraf, Sandimmune, Arpimune Me, Graftin, Imusporin, Panimun Bioral 11 aa (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)- 30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2- methyl-4-hexen-1-yl]-6,9,18,24- tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31- undecaazacyclotritriacontane - 2,5,8,11,14,17,20,23,26,29,32-undecone RGP life sciences, Ranbaxy laboratories, Cipla limited, Ecolity, Allergan, Novartis Transplant (kidney, liver, and heart) rejection, rheumatoid psoriasis arthritis, severe 5–18 hours

16. 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 AMPs(antimicrobial peptides) termed’’ Peptidomimetics ‘’were developed to mimic the bactericidal mechanism.