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PYY(3-36) Analogues: Structure

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PYY(3-36) Analogues: Structure PYY(3-36) analogues: Structure- activity relationships in energy homeostasis A thesis submitted for the degree of Doctor of Philosophy, Imperial College London 2011 Iain David Pritchard Section of Investigative Medicine Division of Diabetes, Endocrinology and Metabolism Department of Medicine Imperial College London Abstract The developed world is currently in the grip of an obesity epidemic. As a result, there is much ongoing research into the development of an effective anti-obesity agent. Peptide YY (PYY) is a 36 amino acid gastro-intestinal hormone released post- prandially by L-cells in the gastro-intestinal tract in proportion to the calorie content of a meal. The predominant form of the hormone found in circulation is the truncated PYY(3-36). Administration of PYY(3-36) at physiological doses to humans has been shown to reduce food intake. However, due to enzymatic degradation these effects are short lived, reducing the hormone’s utility as an anti-obesity pharmaceutical agent. A series of analogues of PYY(3-36) were designed either with amino acid substitutions in specific parts of the peptide sequence and/or with chemical modifications to the native sequence with the aim of increasing resistance to enzymatic activity whilst retaining or even enhancing the peptide’s bioactivity. The analogues were tested for resistance to degradation by different proteolytic enzymes in comparison to natural PYY(3-36). Their affinity to the Y2 receptor, for which PYY(3-36) is a natural agonist was then investigated. Finally, the effects of peripheral administration of selected analogues on food intake in overnight fasted mice were investigated. These studies suggest that PYY(3-36) analogues may be a useful approach for the treatment of obesity, but further development work is required. 2 Declaration of Contributors The majority of the work described in this thesis was performed by the author. Any collaboration and assistance is described below. Chapter 2 – Synthesis and purification of one set of PYY(3-36) analogues were carried out with the assistance of Philip Metcalfe and John Fitzmaurice at Bachem UK Ltd. Chapter 4 – One set of receptor binding studies were carried out with the assistance of James Minnion and Joy Cuenco Shillito. Feeding studies were carried out with the assistance of Ben Field and Anne McGavigan. 3 Acknowledgments I would first like to thank Dr. Kevin Murphy for his supervision of this project. Even from afar, his support and advice were priceless. I would like to express my appreciation to Professor Steve Bloom for giving me the opportunity to conduct this work in his department and to Dr. Stanley Moore at Bachem UK Ltd who helped make it all possible and has provided valuable support throughout. A special thank you to Professor Mohammad Ghatei for his support and supervision. Thanks to everyone at Bachem UK Ltd, both past and present. In particular, special thanks go to Dr. Julie Marley, Neil Harrison, Nicola Adam, Paula Fitzjones, Philip Metcalfe and Greg Brown for their understanding, support and help during the writing up process. Finally, a big thank you to Julie, Aidan and Georgia for helping to keep me sane and smiling during the last few months of this project. I couldn’t have done it without you. 4 Table of contents Abstract.........................................................................................................................2 Declaration of Contributors........................................................................................3 Acknowledgments ........................................................................................................4 Table of contents ..........................................................................................................5 Index of figures...........................................................................................................10 Index of tables ............................................................................................................13 Abbreviations .............................................................................................................14 1 General Introduction.........................................................................................16 1.1 Obesity.........................................................................................................17 1.2 Treatments for obesity .................................................................................18 1.2.1 Bariatric Surgery ...............................................................................18 1.2.2 Pharmaceutical therapies ..................................................................22 1.3 Long term regulation of energy homeostasis...............................................25 1.3.1 Insulin ..................................................................................................25 1.3.2 Leptin ..................................................................................................29 1.4 The central nervous system centres controlling energy homeostasis ..........33 1.4.1 The hypothalamus ..............................................................................33 1.4.2 The arcuate nucleus ...........................................................................34 1.4.3 NPY .....................................................................................................35 1.4.4 AgRP ...................................................................................................37 1.4.5 POMC .................................................................................................38 1.4.6 Other hypothalamic regions ..............................................................39 1.4.7 The brainstem .....................................................................................40 1.4.8 The nucleus tractus solitarius (NTS) ................................................41 1.4.9 The area postrema (AP) ....................................................................41 1.4.10 The dorsal motor nucleus of vagus (DMV) ......................................41 1.5 Gut hormones...............................................................................................42 1.5.1 Ghrelin ................................................................................................43 1.5.2 Cholecystokinin (CCK) .....................................................................46 1.5.3 Glucagon-like peptide-1 (GLP-1) .....................................................47 1.5.4 Oxyntomodulin (OXM) .....................................................................51 1.5.5 Pancreatic polypeptide (PP) ..............................................................53 1.5.6 Peptide YY (PYY) ..............................................................................54 1.6 Gut hormones as obesity therapeutics..........................................................61 1.7 Peptide chemistry.........................................................................................62 1.7.1 Boc/Bzl (Merrifield) SPPS .................................................................65 1.7.2 Fmoc/tBu SPPS ..................................................................................67 1.7.3 Resins ..................................................................................................68 5 1.7.4 Fmoc deprotection .............................................................................72 1.7.5 Coupling ..............................................................................................79 1.7.6 Difficulties in peptide synthesis ........................................................83 1.7.7 Peptide modifications .........................................................................86 1.7.8 Cleavage ..............................................................................................92 1.7.9 Purification .........................................................................................94 1.8 Aims.............................................................................................................98 2 Synthesis and purification of PYY(3-36) analogues .......................................99 2.1 Introduction................................................................................................100 2.1.1 Sites of proteolytic enzyme degradation within PYY(3-36) .........101 2.1.2 N-terminal modifications of PYY(3-36) .........................................101 2.1.3 Binding of PYY(3-36) to the Y 2 receptor .......................................102 2.1.4 The hairpin like structure of PYY(3-36) ........................................103 2.2 Hypothesis and aims ..................................................................................104 2.2.1 Hypothesis .........................................................................................104 2.2.2 Aims ...................................................................................................104 2.3 Materials and methods...............................................................................104 2.3.1 Position 25 and 26 PYY(3-36) analogues .......................................104 2.3.1.1 Peptide design................................................................................104 2.3.1.2 Peptide synthesis............................................................................107 2.3.1.3 Preparation of solution K...............................................................108 2.3.1.4 Peptide cleavage.............................................................................108
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