PPeptides and Peptidases as Targetsesfptides and Peptidases a fofor Therapeutic Interventionr Theapeutic Interventio DDr R A Skidgelr R A Skidgel Biologically Active Peptidesically Active Peptides ACTH Adrenomedullin Amyloid 1 40 Anaphylatoxins Angiotensin II Angiotensin 1 7 Atrial Natriuretic Peptide BAM 12P 18P 22P Bombesin Bradykinin Brain Natriuretic Peptides Buccalin Bursin C Type Natriuretic Peptide Endothelins Met Enkephalin Leu Enkephalin Epidermal Mitosis Inhibiting Peptide Erythropoietin Follicle Stimulating Hormone Galanin Gastric Inhibitory Polypeptide Gastrin Gastrin Releasing Peptide a Gliadorphin Granuliberin R Glucagon Glucagon Like Peptide Growth Factors Caerulein Growth Hormone Calcitonin Growth HormoneCalcitonin Gene RelatedPeptide ReleasingHormone Cardiodilatin Guanylin Carnosine Inhibin CASH Cortical AndrogenInsulin Stimulating Hormone Interleukins Casomorphins Kallidin Cerebellin Kyotorphin Cholecystokinin a Lactorphin Chromostatin Leucokinins CLIP Lipotropin Contraceptive Tetrapeptide Luteinizing Hormone LH Corticotropin Inhibiting Peptide LH Releasing Hormone Corticostatin Magainins Corticotropin ReleasingFactor Mastoparan Cytokines Melanin Concentrating Delta Sleep Inducing Peptide Hormone Dermorphin a Melanocyte Stimulating Dermaseptin Hormone Diabetes Associated Peptide Melanostatin Diazepam Binding Inhibitor Morphine Modulating Dynorphins Neuropeptide Endorphin Motilin a Neoendorphin Neoendorphin Neurokinin A Neurokinin B Neuromedin N Neuropeptide Y Neuropeptide P Neuroprotectin Neurotensin Neutrophil Defensins Orexins Oxytocin PACAP Pituitary Adenylate Cyclase Activating Peptide Pancreastatin Pancreatic Polypeptide Parathyroid Hormone Peptide Histidine Isoleucine Peptide YY Prolactin Proctolin Rigin Secretin Somatostatin Substance P Systemin Thymosin Thyrotropin Thyrotropin Releasing Hormone Tuftsin Urocortin Uroguanylin Vasopressin ADH VIP Vasoactive Intestinal Peptide GENERAL PRINCIPLES OF PEPTIDE METABOLISM 1 A Given Peptide Can be Cleaved by More Than One Peptidase 2 A GIVEN PEPTIDASE CAN HYDROLYZE A VARIETY OF PEPTIDES It is a common misconception that peptidases are peptide specific i e they hydrolyze only one particular peptide This notion is perpetuated by the names given to some of the enzymes e g Angiotensin I Converting Enzyme Enkephalinase Enkephalin Convertase Anaphylatoxin Inactivator etc In fact peptidases are peptide bond specific and can potentially cleave many different peptides EXAMPLE 1 ANGIOTENSIN I CONVERTING ENZYME EXAMPLE 2 NEUTRAL ENDOPEPTIDASE 24 11 3 The Function S Of A Peptidase Will Depend On Its Localization And The Peptide Hormones Available To It In That Location In A Particular Physiological Or Pathological Situation POTENTIAL FUNCTIONS OF NEUTRAL ENDOPEPTIDASE 24 11 NEPRILYSIN NEP Site Peptide Substrate Function Lung Substance P Control Secretion Cough Bronchoconstriction Kidney ANF Bradykinin Regulate Salt and Water Balance Brain Enkephalins Alter Pain Perception Neutrophils Chemotactic Peptides Regulate Chemotaxis Scheme of Peptide Hormone Processing Metabolism RK RR Prohormone Endoprotease Prohormone Convertases Carboxypeptidase Gly PAM Active Peptide Inactive Fragments or Receptor 2 COOH or CONH2 Peptidase s Receptor 1 Peptide hormones are synthesized as larger prohormones In most cases e g neuro and endocrine peptides the prohormone is cleaved at paired basic residues R K R R K K K R by an endoprotease prohormone convertase to release a peptide containing extra C terminal Arg or Lys residues which are then removed by a carboxypeptidase to generate the active peptide In some cases removal of a C terminal basic residue s exposes a C terminal Gly residue which is converted by peptide a amidating monooxygenase PAM in a two step reaction to a C terminal amide group After interaction with a specific receptor the peptide is cleaved by peptidases into inactive fragments or in certain cases into a fragment which may have altered activity and receptor specificity Examples Angiotensin AII and Bradykinin BK AI Inactive Activate AII Active BK P ACE Inactivate BK P Inactive F Modulate BK P R F B2 B1 X B2 GENERATION OF MULTIPLE PROTEINS FROM ONE GENE VIA RNA SPLICING This scheme illustrates the transcription of DNA into a primary RNA transcript that contains intervening sequences introns which are not present in the mature RNA The primary RNA transcript is spliced to remove the introns giving the mature RNA containing only exons The mature RNA contains untranslated regions at both ends and a contiguous sequence in the middle which is translated into protein In some cases alternative splicing of the RNA can lead to more than one type of mRNA resulting in the synthesis of multiple proteins from one gene Page 2 of 15 STRATEGIES FOR DEVELOPING THERAPEUTIC AGENTS I MIMIC THE ACTION OF A PEPTIDE HORMONE A Administer the Peptide ADVANTAGES 1 Highly Potent Agents Active at 10 15M to 10 7M 2 Wide Variety of Biological Activities 3 Readily Synthesized DISADVANTAGES 1 Very Rapidly Degraded by Peptidases 2 Excreted by Kidney 3 Short Duration of Action seconds to minutes 4 Poorly Absorbed from GI Tract 5 Inconvenient Administration e g i v intra nasal 6 Do Not Cross Blood Brain Barrier 7 Expensive to Synthesize B Stimulate Endogenous Synthesis of the Peptide M Advantage Level of the peptide can be specifically increased at its normal site of action M Disadvantage Control of synthesis of most peptide hormones is poorly understood C Block the Degradation by Peptidase s M Advantages 1 Level of the peptide can be specifically increased at its normal site s of action 2 Peptidase inhibitors can be synthesized with good stability and bioavailability M Disadvantages 1 Blocking one peptidase may interfere with the metabolism of more than one peptide 2 Inhibition of more than one peptidase may be needed to block the degradation of a peptide 3 Enhancing general levels of a peptide with multiple actions may produce side effects II BLOCK THE ACTION OF A PEPTIDE A Use a Receptor Antagonist M Advantages 1 Specific actions of a peptide mediated by a single receptor type can be blocked 2 Potential for few unwanted side effects 3 Non peptide antagonists may have good bioavailability and stability M Disadvantages 1 Many peptide receptor antagonists are themselves peptides and suffer from the disadvantages listed above 2 Peptide antagonists have the potential to inhibit peptidase s could increase the concentration of the natural peptide B Block the Synthesis
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