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

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

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  Contents • Introduction • Classification •Advantages and Disadvantages • Method of preparation • Peptidomimetics Drug Design Principle • Chemistry and stereochemistry • Synthesis • Therapeutic value of peptidomimetics
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  Introduction • A smallprotein – 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.
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  Defination  Peptidomimetics are chemicalstructures 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 .
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  Classification Chart No: 1 ClassA • Modified peptides: peptides mainly formed by α-amino acids with minor side chain or backbone alterations. Class B • Modified peptides/ foldamers: peptides with various backbone and side chain alteration also including foldamers. Class C • Structural mimetics: small molecules-like scaffolds that project substituents in analogy to peptide side chains. Class D • Mechanistic mimetics: molecules that mimics the mode of action of a peptides without direct link to its side chains.
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  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
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  Methods of modification
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  Retro-Inverso Peptidomimetics
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  Morphine: a Non-peptidomimetics ForEnkephaline
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  Somatostatine:Early Investigations
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  Peptidomimetic HIV-1 Protease Inhibitors
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  Peptidomimetics Drug DesignPrinciple
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  Chemistry and Stereochemistry
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  Synthesis
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  Therapeutic Value ofPeptidomimetics 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 Pharmaceutical s Antibiotic used to treat systemic and life- threatening infections caused by Gram- positive organisms 8–9 hours Afamelanotid e Scenesse 13 aa Ac-Ser-Tyr-Ser-Nle-Glu-His-D- Phe-Arg- Trp-Gly-Lys-Pro-Val- NH2 Clinuvel Pharmaceutical s 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
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  Recent Advances InPeptidomimetics 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 AMPs(antimicrobial peptides) termed’’Peptidomimetics ‘’were developed to mimic the bactericidal mechanism.