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Leopold Dürrauer Masterarbeit Biologische Chemie

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Leopold Dürrauer Masterarbeit Biologische Chemie MASTERARBEIT / MASTER’S THESIS Title der Masterarbeit / Title of the Master’s Thesis Characterisation of selective human oxytocin/ vasopressin ligands submitted by Leopold Dürrauer, BSc Angestrebter akademischer Grad / in partial fulfilment of the requirements for the degree of Master of Science (MSc) Wien, 2018 / Vienna, 2018 degree program code as it appears on A 066 863 the student record sheet: degree program as it appears on Biologische Chemie the student record sheet: Supervisor: Assoc. Prof. Priv.-Doz. Dr. Christian Gruber, PhD Masterarbeit Biologische Chemie ii Characterisation of selective human oxytocin/vasopressin ligands Acknowledgment I would like to thank Christian Gruber, for believing in me and providing me with the oppor- tunity to carry out this thesis on the other side of the globe. I would also like to thank Peter Keov for his invaluable practical support, Ester Aeiye Odukunle for sharing her asterotocin results, Markus Muttenthaler for synthesis of the peptides used dur- ing this thesis, and Yoonseong Park for his valuable insights into mite oxytocin/vasopressin- like peptide receptors. And, last but not least, I would like to thank my family and friends for their outstanding and unconditional support. 1 Masterarbeit Biologische Chemie 2 Masterarbeit Biologische Chemie Table of Contents Acknowledgment ....................................................................................................................... 1 Table of Contents ....................................................................................................................... 3 Tables ......................................................................................................................................... 8 Figures ........................................................................................................................................ 9 Abbreviations ........................................................................................................................... 11 1 Introduction .................................................................................................................. 12 Oxytocin/ vasopressin signalling system, an overview ...................................... 13 G protein-coupled receptors ............................................................................... 15 1.2.1 GPCRs ...................................................................................................... 15 1.2.2 OTR, V1aR, V1bR and V2R ....................................................................... 17 1.2.3 Selectivity ................................................................................................. 18 Oxytocin, vasopressin and oxytocin/vasopressin-like peptides ......................... 18 1.3.1 Crosstalk ................................................................................................... 19 1.3.2 Evolutionary aspects ................................................................................. 20 1.3.3 Nomenclature ............................................................................................ 20 Agonists and antagonists .................................................................................... 22 1.4.1 Atosiban .................................................................................................... 22 3 Masterarbeit Biologische Chemie 1.4.2 Carbetocin ................................................................................................. 22 1.4.3 Retosiban .................................................................................................. 22 1.4.4 Desmopressin ............................................................................................ 23 1.4.5 Future compounds .................................................................................... 23 Arachnotocin ...................................................................................................... 25 1.5.1 Varroa destructor ...................................................................................... 25 Asterotocin ......................................................................................................... 27 1.6.1 Asterias rubens ......................................................................................... 27 Aims of this thesis .............................................................................................. 28 2 Materials and Methods ................................................................................................. 29 Cloning ............................................................................................................... 30 2.1.1 Overview of the Cloning process ............................................................. 30 2.1.2 Polymerase chain reaction (PCR) ............................................................. 32 2.1.3 Gel purification ......................................................................................... 33 2.1.4 Restriction digests and ligation ................................................................. 35 2.1.5 Transformation ......................................................................................... 36 2.1.6 Plasmid preparation and sequencing ........................................................ 38 2.1.7 Glycerol stocks ......................................................................................... 40 Cell culture ......................................................................................................... 41 2.2.1 Transfection .............................................................................................. 42 Pharmacological assays ...................................................................................... 43 4 Masterarbeit Biologische Chemie 2.3.1 Fluorescence resonance energy transfer ................................................... 44 2.3.2 IP-One assay ............................................................................................. 45 2.3.3 cAMP assay .............................................................................................. 47 Microscopy ......................................................................................................... 48 Bioinformatics .................................................................................................... 49 2.5.1 BLAST ...................................................................................................... 49 2.5.2 Sequence alignments ................................................................................ 49 3 Results .......................................................................................................................... 50 Cloning of a Varroa destructor Arachnotocin Receptor ..................................... 51 3.1.1 Overview .................................................................................................. 51 3.1.2 Arachnotocin polypeptide precursor ........................................................ 51 3.1.3 Receptor identification ............................................................................. 52 3.1.4 Cloning ..................................................................................................... 57 3.1.5 Receptor Pharmacology ............................................................................ 57 3.1.6 Receptor Localization ............................................................................... 60 Peptide Pharmacology ........................................................................................ 62 3.2.1 Overview .................................................................................................. 62 3.2.2 hV1aR ........................................................................................................ 63 3.2.3 hV1bR ........................................................................................................ 65 3.2.4 hV2R ......................................................................................................... 67 3.2.5 OTR .......................................................................................................... 69 5 Masterarbeit Biologische Chemie Schild regression analysis of arachnotocin on hV1aR ........................................ 71 3.3.1 Overview .................................................................................................. 71 3.3.2 Schild results ............................................................................................. 72 Structure-activity relationship of the investigated peptides ............................... 75 3.4.1 Overview .................................................................................................. 75 3.4.2 Multiple Sequence Alignment .................................................................. 75 3.4.3 Commonalities .......................................................................................... 76 3.4.4 Asterotocin and [D-Glu8]-asterotocin ...................................................... 76 3.4.5 Arachnotocin ............................................................................................ 79 4 Discussion .................................................................................................................... 81 Investigation of the Varroa destructor arachnotocin receptor ............................ 82 Human oxytocin/vasopressin receptor pharmacology ....................................... 84
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