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The Identification and Pharmacological Characterisation of Novel Apelin Receptor Agonists in Vitro and in Vivo

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The Identification and Pharmacological Characterisation of Novel Apelin Receptor Agonists in Vitro and in Vivo The Identification and Pharmacological Characterisation of Novel Apelin Receptor Agonists In Vitro and In Vivo by Cai Read Jesus College Experimental Medicine and Immunotherapeutics Research Supervisor: Dr Anthony P. Davenport August 2018 This dissertation is submitted for the degree of Doctor of Philosophy This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text The length of this dissertation does not exceed 60,000 words. Table of Contents Acknowledgements .................................................................................................... i Publications ............................................................................................................... ii Presentations ............................................................................................................ iii Abstract ..................................................................................................................... iv Abbreviations ............................................................................................................ v List of Figures and Tables ..................................................................................... viii 1. Introduction ......................................................................................................... 1 1.1 Background .................................................................................................... 1 1.2 Apelin Receptor Structure .............................................................................. 3 1.3 Apelin Receptor Signalling in the Cardiovascular System .............................. 5 1.4 Endogenous Agonists .................................................................................... 9 1.4.1 Apelin ..................................................................................................... 10 1.4.2 Elabela ................................................................................................... 13 1.5 Synthetic Agonists ........................................................................................ 15 1.5.1 Peptide Modifications ............................................................................. 15 1.5.2 Small Molecules ..................................................................................... 18 1.5.3 Summary ............................................................................................... 19 1.6 Synthetic Antagonists ................................................................................... 21 1.7 Apelin Physiology and Pathophysiology ....................................................... 24 1.7.1 Development.......................................................................................... 24 1.7.2 Cancer ................................................................................................... 24 1.7.3 Fibrosis .................................................................................................. 25 1.7.4 Pulmonary Arterial Hypertension (PAH) and Heart Failure (HF) ............ 27 1.7.5 Obesity and Diabetes ............................................................................ 30 1.7.6 HIV/SIV Co-Receptor ............................................................................. 31 1.7.7 Fluid Homeostasis ................................................................................. 31 1.8 ELA Physiology and Pathophysiology .......................................................... 33 1.8.1 Developmental Roles ............................................................................. 33 1.8.2 Adult Cardiovascular Roles ................................................................... 34 1.8.3 Disease and the Possibility of a Second Receptor for ELA ................... 34 1.9 Knock-out Mouse Models ............................................................................. 36 1.10 Biased Small Molecule Agonists as a Therapeutic Strategy at the Apelin Receptor ............................................................................................ 39 1.11 Albudab™ Platform and Antibodies as a Therapeutic Delivery Strategy ...... 43 1.12 Hypothesis and Aims .................................................................................... 46 2. Methods ............................................................................................................ 47 2.1 Materials ....................................................................................................... 47 2.2 Preparation of Tissue Homogenates ............................................................ 48 2.3 Competitive Radioligand Binding Assays ..................................................... 49 2.4 Cell Signalling Assays .................................................................................. 50 2.4.1 β-Arrestin Assay .................................................................................... 50 2.4.2 cAMP Assay .......................................................................................... 52 2.4.3 Internalisation Assay .............................................................................. 55 2.5 Apoptosis Assay Using Human PAECs ........................................................ 57 2.5.1 Use of Low Passage Number Human PAECs ....................................... 59 2.5.2 Annexin Concentration Optimisation ...................................................... 60 2.5.3 TNFα and CHX Concentration Optimisation .......................................... 62 2.5.4 Data Analysis ......................................................................................... 64 2.5.5 Evaluation .............................................................................................. 65 2.6 Surgical Techniques ..................................................................................... 66 2.6.1 Surgical Procedures to Assess Acute Cardiovascular Responses ........ 66 2.6.2 Surgical Procedures to Measure LVSP and RVSP Following a MCT Prevention Study of PAH .............................................................. 73 2.7 Apelin Enzyme-Linked Immunosorbent Assay ............................................. 75 2.8 Statistical Analysis........................................................................................ 76 3. Identification and Characterisation of CMF-019, the First G Protein Biased Apelin Agonist ...................................................................................... 77 3.1 Introduction .................................................................................................. 77 3.2 Methods ....................................................................................................... 79 3.2.1 Materials ................................................................................................ 79 3.2.2 Competitive Radioligand Binding Assays .............................................. 79 3.2.3 Cell Signalling Assays ........................................................................... 79 3.2.3.1 β-Arrestin Assay .............................................................................. 79 3.2.3.2 cAMP Assay .................................................................................... 79 3.2.3.3 Internalisation Assay ....................................................................... 79 3.2.4 Statistical Analysis ................................................................................. 80 3.3 Results ......................................................................................................... 81 3.3.1 Competitive Radioligand Binding Studies .............................................. 81 3.3.1.1 [Pyr1]apelin-13 Bound to Apelin Receptors ..................................... 81 3.3.1.2 CMF-013, -015, -019 and -021 Bound to the Human Apelin Receptor ............................................................................... 82 3.3.1.3 CMF-019 Bound to Rat and Mouse Apelin Receptors .................... 83 3.3.1.4 CMF-087 Bound to the Human Apelin Receptor ............................. 83 3.3.1.5 MM239 and MM240 Bound to Native Human and Rat Apelin Receptors ...................................................................... 84 3.3.2 Cell Signalling Assays ........................................................................... 85 3.3.2.1 CMF-013, -015, -019 and -021 Displayed G Protein Signalling Bias ................................................................................. 85 3.3.2.2 CMF-087, MM239 and MM240 Displayed Reduced G Protein Signalling Bias Compared to the Parent Molecule, CMF-019 ......... 86 3.3.2.3 Bias Calculations ............................................................................. 86 3.3.3 Summary Tables ...................................................................................
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