Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2012
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| Schlagworte: | |
| Online-Zugang: | Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120920-1127632-1-6 Inhaltsverzeichnis |
| Beschreibung: | XVI, 144 S. Ill., graph. Darst. |
Internformat
MARC
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| 035 | |a (DE-599)BVBBV041375271 | ||
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| 100 | 1 | |a Meyer, Christoph Jürgen |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |c Christoph Jürgen Meyer |
| 264 | 1 | |c 2012 | |
| 300 | |a XVI, 144 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |a München, Techn. Univ., Diss., 2012 | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
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| 856 | 4 | 1 | |u http://mediatum.ub.tum.de/node?id=1127632 |x Verlag |z kostenfrei |3 Volltext |
| 856 | 4 | |u https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120920-1127632-1-6 |x Resolving-System | |
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| 912 | |a ebook | ||
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Datensatz im Suchindex
| _version_ | 1804151467869732864 |
|---|---|
| adam_text | TABLE OF CONTENTS
LIST OF ABBREVIATIONS X
LIST OF FIGURES XV
1 INTRODUCTION 1
1.1 CELL SIGNALING
AND PROTEIN PHOSPHORYLATION 1
1.2 CONTROL OF PHOSPHORYLATION BY PROTEIN KINASES AND PHOSPHATASES 2
1.3 THE PROTEIN TYROSINE PHOSPHATASE (PTP) FAMILY 3
1.4 PTP1B
(PTPN1) AND ITS ROLE IN HUMAN DISEASE 8
1.5 INHIBITORS OF PTP1B 12
1.6 CHEMICAL PROBES TO STUDY PTP1B ACTIVITY 17
2 AIM OF THE PROJECT 19
3 RESULTS 21
3.1 DETERMINATION OF A SUBSTRATE SEQUENCE FOR FURTHER DERIVATIZATION 21
3.1.1 SELECTION OF SUITABLE SUBSTRATE SEQUENCES FOR IN VITRO SCREENING
21
3.1.2 SYNTHESIS OF PHOSPHOPEPTIDES 22
3.1.3 SCREENING OF THE PHOSPHOPEPTIDE LIBRARY 22
3.2 SELECTION OF A NON-HYDROLYZABLE PHOSPHOTYROSINE ANALOGUE 24
3.2.1 EFFICIENT SCALED-UP SYNTHESIS OF
N-A-FMOC-4-PHOSPHONO(DIFLUOROMETHYL)-L-PHENYLALANINE 25
3.2.2 INCORPORATION OF F
2
PMP INTO
PEPTIDES 27
3.3 CYCLIZATION OF F
2
PMP CONTAINING
PEPTIDES 29
3.3.1 CYCLIZATION TRIALS USING THE THIOL-ENE REACTION 29
3.3.2 CYCLIZATION USING THE COPPER CATALYZED AZIDE-ALKYNE CYCLOADDITION
(CUAAC) 33
3.4 BINDING AND INHIBITION STUDIES OF F
2
PMP CONTAINING PEPTIDES 38
3.4.1 MEASUREMENT OF INHIBITORY POTENCIES USING THE PNPP INHIBITION
ASSAY 39
3.4.2 AFFINITY MEASUREMENTS WITH THE FLUORESCENCE POLARIZATION ASSAY 45
3.5 EVALUATION OF THE CELLULAR PENETRATION, STABILITY AND ACTIVITY OF
THE PEPTIDIC INHIBITORS 47
VII
HTTP://D-NB.INFO/1044132205
3.5.1 COMPARISON OF CELLULAR PENETRATION
USING CONFOCAL MICROSCOPY 47
3.5.2 COLOCALIZATION
OF A CELL PENETRATING CF-SRC-P(-2)A SEQUENCE WITH PTP1B 50
3.5.3 STABILITY OF LINEAR VERSUS CYCLIC INHIBITORY
PEPTIDES IN CELL LYSATE AND HUMAN BLOOD SERUM 53
3.6 BIOTINYLATED F
2
PMP CONTAINING
PEPTIDES AS PULL-DOWN TOOLS 55
4 DISCUSSION 65
4.1 SELECTION OF A SUBSTRATE SEQUENCE FOR FURTHER INHIBITOR DEVELOPMENT
65
4.2 EFFICIENT SYNTHESIS OF N-FMOC-F
2
PMP AND
ITS INCORPORATION INTO PEPTIDES 67
4.3 CYCLIZATION OF THE
INHIBITORY PEPTIDE 67
4.4 ANALYSIS AND
BINDING STUDIES OF SRC DERIVED LINEAR AND CYCLIC SEQUENCES 68
4.5 INFLUENCE OF CYCLIZATION ON CELL PERMEABILITY AND STABILITY 73
4.6 APPLICATION OF BIOTINYLATED F
2
PMP
CONTAINING SEQUENCES AS PULL-DOWN TOOLS 74
5 CONCLUSIONS AND
PERSPECTIVES 76
6 SUMMARY 79
7 EXPERIMENTAL
SECTION 81
7.1 GENERAL 81
7.1.1 CHEMICALS 81
7.1.2 INSTRUMENTS 81
7.1.3 BUFFERS AND
MEDIA 83
7.1.4 BIOLOGICAL MATERIAL 85
7.1.5 SOFTWARE 87
7.1.6 CLONING, EXPRESSION
AND PURIFICATION OF RECOMBINANT PROTEINS 87
7.2 EXPERIMENTS AND METHODS TO CHAPTER 3 93
7.2.1 EXPERIMENTS AND
METHODS TO CHAPTER 3.1.2 93
7.2.2 EXPERIMENTS
AND METHODS TO CHAPTER 3.1.3 97
7.3.1 EXPERIMENTS AND
METHODS TO CHAPTER 3.2.1 98
7.3.2 EXPERIMENTS
AND METHODS TO CHAPTER 3.2.2 100
7.4.1 EXPERIMENTS AND
METHODS TO CHAPTER 3.3.1 103
7.4.2 EXPERIMENTS AND
METHODS TO CHAPTER 3.3.2 105
7.5.1 EXPERIMENTS AND
METHODS TO CHAPTER 3.4.1 108
7.5.3 EXPERIMENTS AND
METHODS TO CHAPTER 3.4.2 116
VIII
7.6.1 EXPERIMENTS AND METHODS TO CHAPTER 3.5.1 120
7.6.2 EXPERIMENTS AND METHODS TO CHAPTER
3.5.2 121
7.6.3 EXPERIMENTS AND METHODS TO CHAPTER 3.5.3 122
7.7 EXPERIMENTS AND METHODS TO CHAPTER 3.6 124
8 REFERENCES 133
IX
|
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| spelling | Meyer, Christoph Jürgen Verfasser aut Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors Christoph Jürgen Meyer 2012 XVI, 144 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Techn. Univ., Diss., 2012 (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:91-diss-20120920-1127632-1-6 http://mediatum.ub.tum.de/node?id=1127632 Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120920-1127632-1-6 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026823354&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Meyer, Christoph Jürgen Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| subject_GND | (DE-588)4113937-9 |
| title | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| title_auth | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| title_exact_search | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| title_full | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors Christoph Jürgen Meyer |
| title_fullStr | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors Christoph Jürgen Meyer |
| title_full_unstemmed | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors Christoph Jürgen Meyer |
| title_short | Synthesis, characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| title_sort | synthesis characterization and application of stabilized natural substrates as protein tyrosine phosphatase inhibitors |
| topic_facet | Hochschulschrift |
| url | http://mediatum.ub.tum.de/node?id=1127632 https://nbn-resolving.org/urn:nbn:de:bvb:91-diss-20120920-1127632-1-6 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026823354&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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