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Optimisation of a New Class of Peptide-Based MRI Contrast Agent

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Optimisation of a New Class of Peptide-Based MRI Contrast Agent Optimisation of a New Class of Peptide- Based MRI Contrast Agent Sarah Lauren Newton A thesis submitted to The University of Birmingham For the degree of DOCTOR OF PHILOSOPHY PSIBS Doctoral Training Centre School of Chemistry College of Engineering and Physical Sciences The University of Birmingham August 2017 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract To determine the effect rotational correlation time (τR) has on relaxivity, peptides of different lengths were investigated. Extending the length of the peptide had a negligible impact on folding, stability and inner-sphere water coordination. The relaxivity was found to be the same indicating that τR is not the limiting factor in this class of contrast agent. A peptide was designed with the potential to increase secondary sphere water coordination to the peptide exterior. No change in relaxivity was observed, compared to MB1- 2, due secondary sphere H2O being located at too far from the paramagnetic Gd(III). Secondary sphere water coordination was further investigated when a water channel was identified. The channel allows water to come within close proximity of Gd(III), with the potential to increase relaxivity. D-amino acids were introduced in an attempt to block the water channel, but this had little impact. Finally, the biological activity of the peptides in biological systems was investigated. It was found that increased transmetalation occurred when the Gd(III) binding site was located at the N-terminus of the coiled coil. Cell lines were treated with Gd(MB1-1)3 at MRI relevant concentrations and cell death occurred when treated with clinically relevant concentrations of the metallo peptide. Acknowledgments Firstly I would like to thank my supervisors, Anna Peacock, Melanie Britton and Iain Styles, without your support and guidance this PhD would not have been possible. Your passion for science has driven me to achieve my scientific goals and I appreciate the time and effort you have put in to help me with all aspects of my PhD. Thank you to the PSIBS Doctoral Training Centre for the opportunity to undertake a PhD and for your continual support. I would like to say a big thank you to my PSIBS buddy Becky for your friendship, guidance and encouragement throughout the last four years. Thank you to the members of the Peacock and Britton groups, to the past members for your guidance and advice, and to the current members - it has been a pleasure working with you. Thank you to Josh, your knowledge and passion for science is inspirational and I am so appreciative of the help you have given me in the lab and with writing my thesis. A massive thank you to Louise, I will never forget the support you have given me both in academia and life outside the lab; I couldn’t have done it without you. To Mum, Dad and Jamie, thank you for your enthusiasm and encouragement throughout my education, I hope I have made you proud with what I have achieved. Dad, I am so pleased to follow in your footsteps to become the next Dr Newton. Finally, I have been lucky to meet my boyfriend and best friend, Chris, at the University of Birmingham. Thank you for always being there for me and encouraging me to reach the finish line. i Table of Contents Acknowledgments ..................................................................................................................................... i Abbreviations .......................................................................................................................................... vi Amino Acids ............................................................................................................................................ vii Peptide Sequences ................................................................................................................................... x Awards and Publications ......................................................................................................................... xi Chapter 1: Literature Review .................................................................................................................. 1 1.1 Introduction................................................................................................................................... 1 1.2 The Lanthanides ............................................................................................................................ 1 1.3 Relaxation Theory in MRI .............................................................................................................. 2 1.3.1 T1 Specific Contrast Agents ........................................................................................................ 6 1.3.2 T2 Specific Contrast Agents ........................................................................................................ 7 1.4 Current Gd(III) Contrast Agents ..................................................................................................... 7 1.5 Approaches to Enhanced Contrast ................................................................................................ 8 1.5.1 Water Coordination ................................................................................................................... 9 1.5.2 Water Residency Time and Exchange ...................................................................................... 11 1.5.3 Rotational Correlation Time ..................................................................................................... 13 1.6 Lanthanides as MRI Contrast Agents .......................................................................................... 16 1.7 The Use of Manganese(II) in MRI Contrast Agents ..................................................................... 18 1.8 Peptide-Based Contrast Agents ................................................................................................... 20 1.9 De Novo Design and Coiled-Coil Peptides ................................................................................... 21 1.10 Metal Binding in Coiled-Coil Peptides ....................................................................................... 22 1.11 Lanthanide Binding Coiled-Coil Peptides .................................................................................. 23 1.12 De Novo Designed Lanthanide Coiled-Coils for MRI ................................................................. 25 1.13 Project Aims .............................................................................................................................. 27 Chapter 2: Experimental Techniques .................................................................................................... 30 2.1 Peptide Synthesis and Purification .............................................................................................. 30 2.2 High Performance Liquid Chromatography ................................................................................ 32 2.3 Mass Spectrometry ..................................................................................................................... 33 2.4 Ultra Violet-Visible Spectroscopy ................................................................................................ 34 2.5 Circular Dichroism ....................................................................................................................... 34 2.6 Emission Spectroscopy ................................................................................................................ 36 2.7 Nuclear Magnetic Resonance ...................................................................................................... 37 2.8 Relaxation .................................................................................................................................... 40 ii 2.9 Magnetic Resonance Imaging .................................................................................................... 41 2.9.1 Frequency and Phase Encoding................................................................................................ 42 2.9.2 Resolution and Field of View ................................................................................................... 43 2.9.3 Spin Echo Imaging Sequence ................................................................................................... 43 2.9.4 Image Contrast ........................................................................................................................ 44 Chapter 3: Effect of Peptide Length on Relaxivity and the Effectiveness of MRI Contrast Agents ...... 45 3.1 Introduction................................................................................................................................. 45 3.2 Aims ............................................................................................................................................. 46 3.3 Results and Discussion ...............................................................................................................
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