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The Development of Gut Hormones As Drugs for the Treatment of Obesity

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The Development of Gut Hormones As Drugs for the Treatment of Obesity The Development of Gut Hormones as Drugs for the Treatment of Obesity A thesis submitted for the Degree of Doctor of Philosophy from Imperial College London Joyceline Cuenco 2014 Division of Diabetes, Endocrinology and Metabolism Section of Investigative Medicine Faculty of Medicine 1 ABSTRACT Obesity is an ever-increasing problem with limited effective treatments available that are safe and tolerable. Gut hormones are naturally occurring endogenous satiety factors that are released in response to food consumption. As well as playing an important role in the regulation of appetite, food intake and body weight, they also have roles in glucose disposal, gastric motility, fuel-type utilisation and energy expenditure. These characteristics make gut hormones attractive drugable targets for the treatment of obesity. However, the vulnerability of gut hormones to degradative enzymes results in rapid clearance rates and limited bioactivity which limits their viability as anti-obesity therapies. This work aims to address two important properties to consider when developing gut hormones as drugs: cause of degradation and immunogenicity. Using pancreatic polypeptide (PP), I developed in vitro and in vivo testing systems to identify the physiologically important mechanisms involved in PP degradation. DPPIV and NEP were identified as important enzymes and enzyme-resistant analogues of PP were designed which demonstrated greater efficacy and slower clearance rates. Subcutaneous (SC) administration of foreign exogenous peptides is known to potentially cause immunogenic reactions against the foreign peptide. The dangers of this reaction can range from mild to lethal. Currently peptide therapeutics require SC administration as oral bioavailability is low. Therefore, an aim of my studies was to explore the impact of modifications to PYY with regard to immunogenicity. To do this I assessed the impact of changes to different regions and specific amino acids of PYY. I successfully identified a region of PYY which, when modified, caused immunogenicity and what substitutions resulted in the most changes to immunogenic properties. In summary my work demonstrated that by understanding the causes of peptide clearance and immunogenicity, safer and more efficacious analogues of gut hormones can be designed to take forward as potential treatments for obesity. 2 The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work 3 DECLARATION OF CONTRIBUTORS All of the work in this thesis was performed by the author. All collaborations are listed below. Chapter 3: Development of the PP analogue was in collaboration with Professor Stephen Bloom. Testing of the analogues in animal studies was carried out by the Drug Discovery team, Imperial College (Drs. James Minnion, Tricia Tan, Jordan Baxter, Mike Tilby, Sejal Patel and Miss Claire Gibbard). Dr. James Gardiner assisted in setting up the over-expressing cell lines. Drs. Mélisande Addison and Jordan Baxter assisted in preparations of RBB. MALDI-MS was outsourced to the Proteomic facility (ABC, Imperial College, London, UK). Chapter 4: Development of the PYY analogue was in collaboration with Professor Stephen Bloom. Testing of the analogues in animal studies was carried out by the Drug Discovery team, Imperial College (Drs. James Minnion, Tricia Tan, Mélisande Addison, Mohammed Hankir, Samar Ghourab, Natacha Germain-Zito, and Keisuke Suzuki). Dr. James Gardiner assisted in setting up the over-expressing cell lines. All radioimmunoassays were performed under the guidance and supervision of Professor Mohammad Ghatei who established and maintained all of the assays. Radiolabelled peptides for all competitive assays were also provided by Professor Mohammad Ghatei. 4 ACKNOWLEDGEMENTS I would like to thank Professors Steve Bloom and Mohammad Ghatei for giving me the opportunity to carry out this work and for their supervision and encouragement. Much appreciation to Dr James Minnion for his supervision, continuing guidance and advice. Big thanks to the Drug Discovery Team in all their evolving shapes and guises for all their hard work and assistance. I am particularly grateful to members of the lab for their support and huge amounts of encouragement to the bitter end. A special thank you, of course, to my family and those who have listened regardless. 5 “Just because it binds, doesn’t mean it’s doing anything. Shit sticks to the bottom of your shoe; doesn’t mean it has receptors on it.” - Anon 6 Abbreviations 5-HT 5-hydroxytryptamine or Serotonin 5-HT2C Serotonin receptor type 2C AcN Acetonitrile ACTH Adrenocorticotrophic hormone ADA Anti-drug antibody AgRP Agouti related protein AIB aminoisobutyric acid AMP Adenosine monophosphate AMPA/KA Kainate receptor ANOVA Analysis of variance AP Area postrema ARC Arcuate nucleus ATP Adenosine triphosphate AUC Area under curve BAT Brown adipose tissue BBB Blod brain barrier BDNF Brain-derived BMI Body mass index BPD Biliopancreatic diversion BSA Bovine serum albumin BW Body weight cAMP Cyclic adenosine monophosphate CART Cocaine- and amphetamine-regulated transcript CB1 Canabinnoid receptor 1 CCK Cholecystokinin CHO Chinese hamster ovary CNS Central nervous system CO2 Carbon dioxide CRF Corticotrophin-releasing factor CsCl Caesium chloride CYP Cytochome DMEM Dulbecco’s modified Eagle medium DMF Dimethylformamide DMN Dorsomedial nucleus DMSO Dimethyl sulphoxide DNA Deoxyribonucleic acid DPPIV Dipeptidyl peptidase IV 7 DVC Dorso-vagal comples EDTA Ethylene diamine tetra-acetic acid EE Energy expenditure ELISA Enzyme-linked immunosorbant assay EMA European Medicines Agency EtBr Ethidium bromide Ex-4 Exendin 4 FBS Foetal bovine serum FDA US Food and Drug Administration FGF Fibroblast growth factor FI Food intake Fmoc Fluorenyl Methoxy-Carbonyl FW Food weight GABA Gamma aminobutyric acid GCG Glucagon GDW Glass distilled water GEE Generalised estimating equations GHSR Growth hormone secretagogue receptor GI Gastrointestinal GIP Glucose-dependent insulinotropic peptide GLP-1 Glucagon-like peptide-1 GLP-1r Glucagon-like peptide-1 receptor GLP-2 Glucagon-like peptide-2 GPCR G-protein coupled receptor GRPP Glicentin-related pancreatic polypeptide GTE Glucose tris EDTA HEK Human embryonic kidney HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC High performance liquid chromatography IBMX 3-Isobutyl-1-methylxanthine ICV Intracerebroventricular Insl5 Insulin-like peptide 5 IP Intraperitoneal IV Intravenous LB Lysogeny broth LHA Lateral hypothalamic area MALDI-ToF Matrix-assisted laser desorption/ionisation Time-of-flight MCH Melanin-concentrating hormone MCR Melanocortin receptor MC3r Melanocortin-3 receptor MC4r Melanocortin-4 receptor 8 ME Median eminence MEMRI Manganese-enhanced magnetic resonance imaging MPGF Major proglucagon fragment MPOA Medial preoptic area mRNA Message ribonucleic acid m/z Mass to charge ratio MSH Melanocyte-stimulating hormone NB Naltrexone buproprion NDMA Neurotransmitter glutamate NEP Neprilysin or Neutral endopeptidase 24.11 NHS National health service NICE National institute for health and clinical excellence NPY Neuropeptide Y NTS Nucleus of the solitary tract Ob-Rb Leptin receptor OXM Oxyntomodulin PBS Phosphate buffered saline PC1/2/3 Prohormone convertase PEG Polyethylene glycol PEI Polyethylenimine PMSF Phenylmethylsulphonylfluoride POMC Proopiomelanocortin PP Pancreatic polypeptide PVN Paraventricular nucleus PYY Peptide tyrosine tyrosine RBA Receptor binding assay RBB Renal brush border RIA Radioimmunoassay RIPA Radioimmunoprecipitation assay RLM Rat liver microsomes RNA Ribonucleic acid RT Retention time RYGB Roux–en-Y gastric bypass SC Subcutaneous SDS Sodium dodecyl sulphate SEM Standard error of the mean SP Spacer peptide SPPS Solid phase peptide synthesis T2DM Type 2 diabetes mellitus TAE Tris, acetic acid, EDTA TFA Trifluoroacetic acid 9 UCP-1 Uncoupling protein 1 VIP Vasoactive intestinal peptide VMN Ventromedial nucleus VSG Vertical sleeve gastrectomy WHO World health oranisation Y1/2/4/5r NPY1/2/4/5 receptor 10 TABLE OF CONTENTS ABSTRACT ........................................................................................................................ 2 DECLARATION OF CONTRIBUTORS .................................................................................... 4 ACKNOWLEDGEMENTS ..................................................................................................... 5 ABBREVIATIONS ............................................................................................................... 7 TABLE OF CONTENTS ...................................................................................................... 11 INDEX OF FIGURES .......................................................................................................... 18 INDEX OF TABLES............................................................................................................ 25 CHAPTER 1 ..................................................................................................................... 27 GENERAL INTRODUCTION ....................................................................................................................
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