Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases:
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
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[2017]
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| Beschreibung: | XVIII, 231 Seiten Illustrationen, Diagramme 30 cm |
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| 100 | 1 | |a Bastos Lima, Allan |e Verfasser |0 (DE-588)1139068962 |4 aut | |
| 245 | 1 | 0 | |a Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |c presented by M.Sc. Allan Bastos Lima |
| 264 | 1 | |a Heidelberg |c [2017] | |
| 300 | |a XVIII, 231 Seiten |b Illustrationen, Diagramme |c 30 cm | ||
| 336 | |b txt |2 rdacontent | ||
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| 502 | |b Dissertation |c Ruperto-Carola University of Heidelberg |d 2017 | ||
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| _version_ | 1804178115110371328 |
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| adam_text | PEPTIDE-HYBRIDS AS DUAL INHIBITORS OF THE
DENGUE AND WEST NILE VIRUS PROTEASES
REFEREES:
PROF. DR. CHRISTIAN D. KLEIN
PROF. DR. R ALF BARTENSCHLAGER
TABLE OF CONTENTS
ABSTRACT XVII
ZUSAMMENFASSUNG XVIII
1 INTRODUCTION 1
1.1 DENGUE VIRUS 1
1.2 WEST NILE VIRUS 3
1.3 DENV, WNV, ZIKV AND YFV IN BRAZIL 4
1.4 VACCINE AND CURRENT THERAPY 7
1.5 SOME FEATURES OF THE FLAVIVIRAL RNA GENOME 8
1.6 FLAVIVIRAL NS2B-NS3 SERINE PROTEASE: THE ANTIVIRAL TARGET 10
1.7 BRIEF HISTORICAL ASPECT OF PROTEASE INHIBITORS 13
1.8 STATE OF THE ART ON DENV AND WNV PROTEASE DUAL INHIBITORS 15
1.8.1 DENV PROTEASE INHIBITORS 16
1.8.2 WNV PROTEASE INHIBITORS 18
1.8.3 DUAL INHIBITORS OF THE DENV AND WNV PROTEASES 21
2 DESCRIPTION OF THE PROBLEM 26
3 AIM OF THE WORK 27
4 STRATEGIES AND APPROACHES 28
4.1 STRUCTURE-BASED DRUG DESIGN (SBDD) 28
4.2 FRAGMENT-BASED DRUG DESIGN (FBDD) 30
4.2.1 FRAGMENT GROWING 30
4.2.2 FRAGMENT MERGING 32
4.2.3 BIOISOSTERISM 33
4.3 SYNTHETIC APPROACHES 35
4.3.1 NITROGEN HETEROCYCLES 35
4.3.2 COPPER-CATALYZED AZIDE-ALKYNE CYCLOADDITION (CUAAC) 36
4.3.3 SOLID-PHASE PEPTIDE SYNTHESIS (SPPS) 37
4.4 INHIBITION ASSAYS AND BINDING MODE 39
4.4.1 SELECTIVITY 39
4.4.2 BINDING MODE: TRYPTOPHAN FLUORESCENCE-QUENCHING ASSAY 39
4.4.3 KINETICS STUDIES 40
5 RESULTS AND DISCUSSION
42
6 DUAL INHIBITORS OF THE DENY AND WNV PROTEASES 43
6.1 OVERVIEW OF THE DESIGN 44
6.2 CHEMISTRY 45
6.3 IN VITRO PROTEASE INHIBITION ASSAYS 47
6.4 STRUCTURE ACTIVITY RELATIONSHIP (SAR) STUDIES 50
6.5 TRYPTOPHAN FLUORESCENCE QUENCHING ASSAY 51
6.6 KINETICS STUDIES 51
6.7 ANTIVIRAL ACTIVITY IN CELL CULTURE 52
6.8 DOCKING STUDIES 53
7 MINOR MODIFICATIONS AT THE N - AND C-TERMINUS 57
7.1 BACKGROUND 57
7.2 CHEMISTRY 57
7.3 IN VITRO PROTEASE INHIBITION ASSAYS 58
7.3.1 POLAR GROUPS AT THE N-TERMINUS 58
7.3.2 GLYCIN AND D-PHENYLGLYCIN AT THE C-TERMINUS 60
8 BOUNDARIES OF THE S
3
/S
4
SUB-SITE EXTENSION 64
8.1 OVERVIEW OF THE DESIGN 64
8.1.1 FRAGMENT GROWING 64
8.1.2 MOLECULAR SIMPLIFICATION 65
8.2 CHEMISTRY 66
8.3 IN VITRO PROTEASE INHIBITION ASSAYS AND SAR 67
8.3.1 FRAGMENT GROWING 67
8.3.2 MOLECULAR SIMPLIFICATION 70
8.4 BIOISOSTERISM: IMPROVING THE ACTIVITY WITH A NOVEL CAP FRAGMENT A 72
8.4.1 IN VITRO PROTEASE INHIBITION ASSAYS AND SAR 73
8.5 KINETICS, ANTIVIRAL ACTIVITY IN CELL CULTURE, AND DOCKING STUDIES 76
9 SELECTIVITY TOWARDS DENY PROTEASE 77
9.1 OVERVIEW OF THE DESIGN 77
9.2 CHEMISTRY 78
9.3 IN VITRO PROTEASE INHIBITION ASSAYS AND SAR 80
9.3.1 PRECURSORS OF THE CAPS 80
9.3.2 PHENOXYPHENYL ANALOGS 81
9.3.3 NAPHTHYL ANALOGS 83
9.3.4 NICOTINYL ANALOGS 83
9.4 KINETICS, ANTIVIRAL ACTIVITY IN CELL CULTURE, AND DOCKING STUDIES 85
10 FINAL INHIBITORS 86
10.1 OVERVIEW OF THE DESIGN 86
10.2 CHEMISTRY 87
10.3 IN VITRO PROTEASE INHIBITION ASSAYS AND SAR 89
10.4 TRYPTOPHAN FLUORESCENCE QUENCHING ASSAY 95
10.5 KINETICS STUDIES 96
10.6 ANTIVIRAL ACTIVITY IN CELL CULTURE AND PERMEABILITY 100
10.7 DOCKING STUDIES 104
11 CONCLUSIONS AND OUTLOOK 109
12 ADDITIONAL WORK 111
12.1 CONVERSION OF NITRILES INTO AMIDES UNDER MICROWAVE IRRADIATION 111
12.1.1 BACKGROUND 111
12.1.2 CHEMISTRY 111
12.1.3 OUTLOOK 113
12.1.4 CONCLUSION 113
12.2 CYCLIC PEPTIDE-HYBRIDS 114
12.2.1 BACKGROUND 114
12.2.2 DESIGN 114
12.2.3 CHEMISTRY 115
12.2.4 RESULTS AND DISCUSSION 118
12.2.5 OUTLOOK 119
12.2.6 CONCLUSION 119
13 EXPERIMENTAL 120
13.1 REAGENTS AND SOLVENTS 120
13.2 EQUIPMENT AND ANALYTICAL METHODS 120
13.3 MOLECULAR BIOLOGY AND BIOCHEMISTRY 121
13.3.1 EXPRESSION AND PURIFICATION OF THE VIRAL PROTEASES 121
13.3.2 FRET SUBSTRATES SYNTHESIS 122
13.3.3 DENY AND WNV PROTEASE RELATIVE INHIBITION ASSAY 123
13.3.4 DENY AND WNV PROTEASE ASSAYS FOR IC
50
DETERMINATION 123
13.3.5 DETERMINATION OF THE DISSOCIATION CONSTANT (KI) 124
13.3.6 HPLC-BASED DENY AND WNV PROTEASE ASSAYS 124
13.3.7 THROMBIN ASSAY 125
13.3.8 TRYPSIN ASSAY 125
13.3.9 TRYPTOPHAN FLUORESCENCE QUENCHING ASSAY 126
13.3.10 PARALLEL ARTIFICIAL MEMBRANE PERMEABILITY ASSAY (PAMPA) 126
13.3.11 CELL VIABILITY ASSAY 127
13.3.12 VIRUS YIELD REDUCTION ASSAY 127
13.3.13 CELL-BASED MEASUREMENT O F CYTOTOXICITY AND PROTEASE INHIBITION
128
13.4 CHEMISTRY 129
13.4.1 GENERAL PROCEDURE FOR THE SYNTHESIS OF INTERMEDIATES AND CAPS 129
13.4.2 GENERAL PROCEDURE FOR THE SYNTHESIS OF ARTIFICIAL AMINO ACIDS 132
13.4.3 GENERAL PROCEDURE FOR THE SYNTHESIS O F PEPTIDE-HYBRIDS 135
13.5 ANALYTICAL DATA FOR NON-PEPTIDIC COMPOUNDS 137
13.5.1 COMPOUNDS FROM CHAPTER 6 137
13.5.2 COMPOUNDS FROM CHAPTER 7 145
13.5.3 COMPOUNDS FROM CHAPTER 8 146
13.5.4 COMPOUNDS FROM CHAPTER 9 156
13.5.5 COMPOUNDS FROM TOPIC 12.1 167
13.5.6 COMPOUNDS FROM TOPIC 12.2 168
13.6 HRMS AND PURITY DATA FOR PEPTIDE-HYBRIDS 169
13.7 MOLECULAR MODELING 172
REFERENCES 173
APPENDIX 211
A. COMPLIMENTARY TABLES FOR MOLECULAR MODELING FROM CHAPTER 6 211
B. INHIBITORY ACTIVITY OF REPRESENTATIVE CAPS - CHAPTERS 7, 8 AND 9. 213
C. COMPARATIVE TABLE WITH STRUCTURE AND ICZO OF SELECTED PEPTIDE-HYBRIDS
215
D. COMPOUNDS EVALUATED USING PAMPA - CHAPTER 10 217
E. COMPLIMENTARY TABLES FOR MOLECULAR MODELING FROM CHAPTER 10 218
F. COMPLIMENTARY PICTURES FOR DOCKING STUDIES FROM CHAPTER 10 224
G. PROTOCOL FOR THE SPPS IN 2-CTC RESIN - TOPIC 12.2 226
H. STRUCTURE AND MASS ANALYSIS OF CYCLIC PEPTIDES - TOPIC 12.2 228
ABBREVIATIONS 229
|
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| author | Bastos Lima, Allan |
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| indexdate | 2024-07-10T07:58:50Z |
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| spelling | Bastos Lima, Allan Verfasser (DE-588)1139068962 aut Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases presented by M.Sc. Allan Bastos Lima Heidelberg [2017] XVIII, 231 Seiten Illustrationen, Diagramme 30 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Ruperto-Carola University of Heidelberg 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1138927945/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030067069&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Bastos Lima, Allan Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |
| subject_GND | (DE-588)4113937-9 |
| title | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |
| title_auth | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |
| title_exact_search | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |
| title_full | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases presented by M.Sc. Allan Bastos Lima |
| title_fullStr | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases presented by M.Sc. Allan Bastos Lima |
| title_full_unstemmed | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases presented by M.Sc. Allan Bastos Lima |
| title_short | Peptide-hybrids as dual inhibitors of the dengue and West Nile virus proteases |
| title_sort | peptide hybrids as dual inhibitors of the dengue and west nile virus proteases |
| topic_facet | Hochschulschrift |
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