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Understanding the Transport Mechanism of BBB Peptide Shuttles: Thrre and Miniap-4 As Case Studies

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Understanding the Transport Mechanism of BBB Peptide Shuttles: Thrre and Miniap-4 As Case Studies Understanding the transport mechanism of BBB peptide shuttles: THRre and MiniAp-4 as case studies Cristina Fuster Juncà ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Programa de doctorat de Química Orgànica Understanding the transport mechanism of BBB peptide shuttles: THRre and MiniAp-4 as case studies Cristina Fuster Juncà Tesis doctoral dirigida per: Dra. Meritxell Teixidó Turà Dra. Macarena Sánchez IRB Barcelona Navarro Programa de química i biología IRB Barcelona estructural Programa de química i biología estructural Tutor: Prof. Ernest Giralt Lladó Universitat de Barcelona Facultat de Química - Departament de Química Inorgànica i Orgànica Barcelona, 2019 You cannot hope to build a better world without improving the individuals. To that end, each of us must work for our own improvement. Marie Curie CONTENTS ABBREVIATIONS .......................................................................................................... i INTRODUCTION .......................................................................................................... 1 1.1 - The blood-brain barrier ......................................................................................... 4 1.2 - Drug delivery to the brain ..................................................................................... 7 1.3 - Transport mechanism of different BBB-shuttles .................................................. 9 1.3.1 - Passive transport mechanism ......................................................................... 9 1.3.2 – Active transport mechanisms ........................................................................ 9 1.4 - Assessing BBB transport in cellular models ...................................................... 16 1.4.1 – Passive diffusion BBB models .................................................................... 16 1.4.2 – Endocytosis BBB-models ........................................................................... 17 1.4.3 - Cell-based BBB transport models ................................................................ 21 1.5 - Perspectives ........................................................................................................ 24 OBJECTIVES ............................................................................................................... 25 RESULTS AND DISCUSSION ................................................................................... 29 THR and THRre ....................................................................................................... 31 Biophysical characterization of the THR and THRre interaction with the transferrin receptor .................................................................................................................... 35 Photocrosslinking as a tool to elucidate the THR/THRre-TfR binding site ........... 29 Pharmacokinetic studies of THRre and analogues .................................................. 55 MiniAp-4 .................................................................................................................... 67 Evaluation of proline cis-trans ratio as tool to fine-tune transport .......................... 71 Quantum dots as a tool to study the BBB-shuttle uptake ........................................ 81 Elucidation of the mechanism of internalization ..................................................... 91 Photocrosslinking studies to study the mechanism of internalization................... 105 CONCLUSIONS ......................................................................................................... 117 MATERIALS AND METHODS ............................................................................... 121 PRODUCT CHARACTERIZATION ...................................................................... 143 APPENDIX ................................................................................................................. 159 REFERENCES ........................................................................................................... 188 ABBREVIATIONS Abbreviations aa amino acid ACN acetonitrile AcOH acetic acid AMT adsorptive-mediated transcytosis Apo apolipoprotein ATP adenosine triphosphate AuNP gold nanoparticle BBB blood-brain barrier BBBCM cell-based BBB model Boc tert-butoxycarbonyl BSA bovine serum albumin cF carboxyfluorescein cy5 cyanine-5 CMT carried-mediated transport CNS central nervous system COSY correlation spectroscopy CPP cell-penetrating peptide CSF cerebrospinal fluid CTX chlorotoxin CuAAC copper-catalysed azide-alkyne cycloaddition Da dalton Dap 2,3-diaminopropionic acid DCM dichloromethane DIEA N,N-diisopropylethylamine DIC diisopropylcarbodiimide DMEM Dulbecco’s modified eagle medium DMF dimethylformamide DMSO dimethylsulfoxide dSTORM direct stochastic optical reconstruction microscopy DTT D,L-dithiothreitol EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride i Abbreviations EDTA ethylenediaminetetraacetic acid EGF epidermal growth factor EGFR epidermal growth factor receptor ELISA enzyme-linked immunosorbent assay eq equivalent ESI electrospray ionization FBS fetal bovine serum Fmoc 9-fluorenylmethoxycarbonyl HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid HOAt 1-hydroxy-7-azabenzotriazole HPLC high performance liquid chromatography HPLC-MS high-performance liquid chromatography with mass spectrometry detection HSQC heteronuclear single quantum coherence spectroscopy KD dissociation constant ICP inducing-coupled plasma GFP green fluorescent protein GM1 monosialotetrahexosylganglioside IAA iodoacetamine i.v. intravenous LAT large neutral amino acid transporter LDL low-density lipoprotein LDLR low-density lipoprotein receptor LY Lucifer yellow mAb monoclonal antibody MeOH methanol MS mass spectrometry MW molecular weight nAChR nicotinic acetylcholine receptor NaPi sodium phosphate NHS N-hydroxysuccinimide NMR nuclear magnetic resonance ii Abbreviations NOE nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy NP nanoparticle PAGE polyacrylamide gel electrophoresis PAMPA parallel artificial membrane permeability assay Papp apparent permeability PBS phosphate-buffered saline PDA photodiode array PEG polyethylene glycol PFA paraformaldehyde PK pharmacokinetics PyBOP 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium QDot quantum dot RH Ringer HEPES RMT receptor-mediated transcytosis RNA ribonucleic acid ROI region of interest RT room temperature SAW surface acoustic wavelength SD standard deviation SDS sodium dodecylsulfate SEC size exclusion chromatography SPPS solid-phase peptide synthesis STD saturation transfer difference TBTU O-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate tBu tert-butyl TCEP tris(2-carboxyethyl)phosphine TEER transendothelial electrical resistance TEM transmission electron microscopy TFA trifluoroacetic acid Tf transferrin TfR transferrin receptor iii Abbreviations TIS triisopropylsilane TJ tight junction TOCSY total correlation spectroscopy tR retention time Trt trityl UPLC ultra-high performance
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