Proteases as targets for therapy: [with 16 tables]
Gespeichert in:
| Format: | Buch |
|---|---|
| Sprache: | English |
| Veröffentlicht: |
Berlin [u.a.]
Springer
2000
|
| Schriftenreihe: | Handbook of experimental pharmacology
140 |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XXVIII, 410 S. Ill., graph. Darst. |
| ISBN: | 3540661182 |
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| 300 | |a XXVIII, 410 S. |b Ill., graph. Darst. | ||
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Datensatz im Suchindex
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| adam_text | Contents
Section I. Human Immunodeficiency Virus Protease Inhibitors
CHAPTER 1
The Road to Fortovase. A History of Saquinavir, the First Human
Immunodeficiency Virus Protease Inhibitor
S. Redshaw, N.A. Roberts, and G.J. Thomas. With 5 Figures 3
A. Background 3
I. Present Scale of the Acquired Immunodeficiency Syndrome
Pandemic 3
II. Identification of the Cause of AIDS 3
III. Search for a Cure 4
IV. Identification and Characterisation of HIV Protease 4
B. Roche Inhibitor Program 6
I. Enzyme Assays 7
II. Inhibitor Design 7
III. Selectivity 10
IV. Antiviral Activity 11
V. Combination Studies 11
VI. Resistance 12
VII. Safety and Pharmacokinetics 12
C. Early Clinical Studies 13
I. Absorption and Metabolism 13
II. Efficacy 13
III. Tolerability 14
D. Approval and Beyond 14
I. Incidence of Resistance in Clinical Use 15
II. Immune Function and Opportunistic Infections 15
III. Fortovase a New Formulation 16
E. Outlook 16
References 17
I
XVIII Contents
CHAPTER 2
Clinical Experience with Human Immunodeficiency Virus Protease
Inhibitors: Antiretroviral Results, Questions and Future Strategies
S. Vella. With 1 Figure 23
A. Introduction 23
B. Activity on Immunological and Virological Markers,
and Clinical Efficacy 24
C. Clinical Implications of Resistance to Pis 25
D. Place of Pis in Current Treatment Strategies 27
I. How to Start Antiretroviral Therapy and When to Make
the Decision to Start Treatment 28
E. Future Directions 28
References 30
CHAPTER 3
The Nature of Resistance to Human Immunodeficiency Virus Type 1
Protease Inhibitors
M. Valliancourt, W. Shao, T. Smith, and R. Swanstrom.
With 2 Figures 33
A. Introduction 33
B. Selection for Resistance: in Vitro and in Vivo Comparison 33
C. Biochemical Basis for Resistance 38
D. Different Classes of Resistance Mutations in the Protease 39
E. Cleavage Site Mutations 40
F. Cross Resistance 41
G. Concepts for Salvage Therapy 41
H. Summary 43
References 44
CHAPTER 4
The Next Generation of Human Immunodeficiency Virus Protease
Inhibitors: Targeting Viral Resistance
E.S. Furfine. With 3 Figures 49
A. Human Immunodeficiency Virus Protease Inhibitors:
Advancements in the Treatment of Human Immunodeficiency
Virus Disease 49
I. Current Status of Human Immunodeficiency Virus
Protease Inhibitors 49
II. Two Strategies to Reduce Viral Resistance to Pis 50
B. Strategy 1: Combination Therapy. Maximal Reduction
of Viral Load to Retard Development of Resistance 51
I. Theory and Background 51
Contents XIX
II. Limitations 52
III. Improvement of Strategy 1: Exploiting Currently Available
; Inhibitors 53
1. Approaches to Improving Patient Adherence 53
2. Reducing Resistance Development by Treatment
with Multiple Pis 54
IV. The Next Generation of Inhibitors: the Benefits
of Increasing Potency 55
C. Strategy 2: Designing Drugs to Inhibit Pi Resistant Viruses 56
I. Viral Resistance to Pis 56
II. Pi Resistant Virus: What s the Real Target? 56
III. The Role of Mutations 57
1. Mutations in the Protease Gene 57
2. Mutations Outside of the Protease Gene 59
3. Viral Fitness 59
IV. The Mechanism of Reduction of PI Binding Affinity
to Resistant Protease 60
1. Structural Evaluation 60
2. Kinetic Evaluation 64
V. Chemical Strategies to Inhibit Resistant HIV Protease .... 65
D. Suggestions for Future Therapeutic Strategies 66
References 66
Section II. Other Viral (Non HIV) Protease Inhibitors
CHAPTER 5
The Proteinases Encoded by Hepatitis C Virus as Therapeutic Targets
C. Steinkuhler, U. Koch, R. De Francesco, and A. Pessi.
With 4 Figures 75
A. Introduction 75
B. The NS3 Proteinase 78
I. Structure of the NS3 Proteinase 78
1. The NS3 Proteinase is a Chymotrypsin Like Serine
Proteinase 78
2. A Zinc Binding Site in the NS3 Serine Proteinase
Domain 80
3. Substrate Specificity of NS3 Serine Proteinase 81
II. Inhibitors of the NS3 Proteinase 82
1. Noncompetitve Inhibitors 82
2. Active Site Directed Inhibitors 83
a) Substrate Analogues 83
b) Product Analogues 84
c) Serine Trap Inhibitors 87
Xx Contents
C. The NS2/3 Proteinase 87
References 90
CHAPTER 6
The Human Herpes Virus Proteases
C.E. Dabrowski, X. Qiu, and S.S. Abdel Meguid.
With 10 Figures 95
A. Introduction 95
B. Background 96
C. Three Dimensional Structures 98
I. Overall Fold 98
II. Dimer Interface 99
III. Catalytic Triad 101
IV. The Oxyanion Hole 103
V. Implications for the Catalytic Mechanism 104
D. Ligands 104
I. Substrates 105
II. Assays 107
III. Inhibitors 107
1. Peptide and Peptidomimetic Inhibitors 107
2. Non Peptidic Inhibitors 108
3. Natural Product Inhibitors 109
E. Cell Based Activity of Protease Inhibitors 110
F. Perspective 110
References Ill
CHAPTER 7
The 3C Proteinases of Picomaviruses and Other Positive Sense,
Single Stranded RNA Viruses
E.M. Bergmann and M.N.G. James. With 4 Figures 117
A. Introduction 117
B. Picornaviridae 118
C. Other Families of Positive Sense, Single Stranded
RNA Viruses 119
I. Caliciviridae 119
II. Coronaviridae 120
III. Others 120
D. Functions of Viral Proteinases in Positive Sense, Single Stranded
RNA Viruses 121
I. The Picornaviral Life Cycle 121
j Contents XXI
I
II. Proteolytic Processing of the Viral Polyprotein 123
III. Regulation of Capsid Assembly by Proteolytic Cleavages
of the Capsid Protein Precursors 124
IV. Inhibition of Cellular Functions by Proteolytic Cleavages
of Host Cell Proteins 124
E. The 3C Proteinases 125
I. Structure 125
II. Specificity and Substrate Binding 126
III. Enzymatic Mechanism 129
IV. Autocatalytic Excision of the 3C Proteinases 131
V. Other Functions of the Picornaviral 3C Gene Product 131
F. Inhibition of 3C Proteinases 132
I. Effect of 3C Proteinase Inhibitors on
! Viral Replication 132
I II. Strategies for Design of 3C Proteinase Inhibitors 133
III. Inhibitors of the Chymotrypsin Like Cysteine
Proteinases 135
G. Summary and Outlook 136
References 136
CHAPTER 8
Adenovirus Proteinase Antiviral Target for Triple Combination
Therapy on a Single Enzyme: Potential Inhibitor Binding Sites
W.F. Mangel, D.L. Toledo, M.T. Brown, J. Ding, R.M. Sweet,
D.L. Barnard, and W.J. McGrath. With 7 Figures 145
A. Virus Coded Proteinases as Targets for Antiviral Therapy 145
I. Adenovirus and Its Proteinase in the Virus Life Cycle 145
II. The AVP as a Model System for Antiviral Agents 146
B. Biochemistry of the AVP 146
I. Cloning of the Gene and Development of an Assay
for the Adenovirus 2 Proteinase 146
II. Discovery and Characterization of Two Cofactors 147
III. Binding Interactions among the Cofactors 147
1. AVP Binding to pVIc in the Absence and Presence
of DNA 147
2. AVP pVIc Complex Binding to DNA 147
IV. Roles of AVP Cofactors in Virus Maturation 149
C. Crystal Structure of the Adenovirus 2 Proteinase Complexed
with pVIc 150
D. Potential Inhibitor Binding Sites 152
I. Active Site 152
II. DNA Binding Sites 153
XXII Contents
III. pVIc Binding Sites 153
E. Summary and Prospects 155
References 156
CHAPTER 9
Proteinases as Virulence Factors in Bacterial Diseases and as Potential
Targets for Therapeutic Intervention with Proteinase Inhibitors
J. Potempa and J. Travis 159
A. Introduction 159
B. Common Themes in Bacterial Virulence 159
I. Host Defenses Against Bacterial Pathogens 159
II. Virulence Factors 160
C. Bacterial Proteinases as Potential Virulence Factors 160
I. Distribution of Proteinases among Pathogens 160
II. Potential Targets for Bacterial Proteinases 163
1. Inactivation of Host Proteinase Inhibitors 163
2. Direct and Indirect Degradation
of Connective Tissue 163
3. Dysregulation of Proteinase Cascades 164
a) Kallikrein Kinin Cascade 164
b) Blood Coagulation Cascade 165
c) Fibrinolysis Cascade 166
d) Complement Cascade 167
4. Degradation of Immunoglobulin Function 168
5. Dysregulation of Cytokine Networking Systems 169
6. Virus Activation 170
7. Proteolytic Activity of Bacterial Toxins 171
a) Clostridium Neurotoxins 171
b) Anthrax Lethal Factor 171
c) Epidermolytic (Exfoliative) Toxins of S. Aureus 172
D. Dilemmas in Considering Bacterial Proteinases as Targets
for Antibacterial Chemotherapy 172
E. Paradigms for Testing Proteinase Inhibitors as Therapeutic
Agents 173
I. P Aeruginosa Infections 173
II. 5. Pyogenes Infections 174
III. Diseases Caused by Proteolytic Toxins 176
IV. Periodontal Disease 176
V. Plague 178
F. Bacterial Proteinases to the Rescue 179
G. Conclusions 180
References 180
j Contents XXIII
I
CHAPTER 10
Parasite Proteases as Targets for Therapy
J.H. McKerrow, C.R. Caffrey, and J.P. Salter. With 1 Figure 189
A. Introduction 189
B. Metalloproteases 189
I. Parasite Aminopeptidases 190
II. Parasite Metalloproteases and Tissue Invasion 191
III. The Protease gp63 191
IV. Is gp63 a Logical Target for Development of Protease
Inhibitors as Therapy? 193
V. Future Development of Metalloprotease Inhibitors
Targeting Parasite Proteases 193
C. Cysteine Proteases 194
I. Irreversible Inhibitors 194
II. Reversible Inhibitors 197
D. Serine Proteases 198
I. Cercarial Elastase, an Example of a Parasite Larval Serine
Protease 199
II. Other Potential Serine Protease Targets 199
E. Aspartyl Proteases 199
I. Plasmepsins I and II 200
II. The Indirect Discovery of an Antiparasitic Protease
Inhibitor 201
References 201
Section III. (Non Viral) Proteases Involved in Diseases
CHAPTER 11
Host Proteinases as Targets for Therapeutic Intervention
J.C. Cheronis 207
A. Introduction 207
B. History 212
C. Section Overview 213
References 214
CHAPTER 12
The Role of Metalloprotease Inhibitors in Cancer and Chronic
Inflammatory Diseases
H.S. Rasmussen and K.P. Lynch. With 2 Figures 221
A. Introduction 221
B. MMP Expression in Disease 222
XXIV Contents
I. Cancer 222
II. Arthritis 223
III. Inflammatory Bowel Disease 223
IV. Atherosclerosis 223
C. General Considerations in the Development of MMPIs 224
D. Preclinical Evidence of Anti Tumor Activity of MMPIs 226
E. Clinical Studies with MMPIs 227
I. Design Considerations in Cancer 227
II. Batimastat 228
III. Marimastat 228
IV. Other MMP Inhibitors 230
F. Clinical Studies in Non Cancer Indications 230
G. Conclusions 231
References 231
CHAPTER 13
The Tumor Necrosis Factor a Converting Enzyme
J.D. Becherer, M.H. Lambert, and R.C. Andrews.
With 4 Figures 235
A. Biology of Tumor Necrosis Factor 235
I. Historical Perspective 235
II. The Role of TNF in Inflammatory Diseases 236
B. Characterization of the TNF a Converting Enzyme 236
I. Cell Secretion of TNF a 236
II. Purification and Cloning of TNF a Converting Enzyme 237
III. Structural Features of TACE 238
C. Inhibitors of TACE and TNF a Secretion 245
I. MMP Inhibitors and TACE 245
II. In Vivo Studies with TACE Inhibitors 250
D. TACE and Membrane Protein Secretases 251
I. TACE Mediated Shedding Events 251
II. Other Putative Sheddases 252
References 253
CHAPTER 14
Serine Elastases in Inflammatory and Vascular Diseases
J.C. Cheronis and M. Rabinovitch. With 5 Figures 259
A. Introduction 259
I. Neutrophil Elastase 260
II. Proteinase 3 261
III. Endogenous Vascular Elastase 261
IV. Endothelial Cell Elastase 262
I Contents XXV
B. Serine Elastases and Inflammation 262
C. Serine Elastases and Vascular Diseases 264
D. Potential Clinical Targets for Serine Elastase Inhibition 268
I. Restenosis, Atherosclerosis and Transplant
Vasculopathy 269
II. Myocardial Infarction 270
III. Stroke 270
IV. Bronchopulmonary Dysplasia 271
E. Summary/Conclusion 271
References 271
CHAPTER 15
Inhibitors of Thrombin and Factor Xa
A.H. Schmaier. With 3 Figures 277
A. Introduction 277
B. Thrombin Inhibitors 280
I. Direct Thrombin Inhibitors 281
1. Naturally Occurring Thrombin Inhibitors
in Humans 281
2. Naturally Occurring or Synthetic Thrombin Inhibitors
Applied to Man 282
a) Active Site Inhibitors 282
b) Active Site and Exosite I Inhibitors 284
c) Exosite I Inhibitors 285
d) Active Site and Exosite II Inhibitors and Exosite II
Inhibitors Alone 286
II. Indirect Thrombin Inhibitors 287
C. Factor Xa Inhibitors 289
I. Naturally Occurring Factor Xa Inhibitors in Humans 289
II. Naturally Occurring or Synthetic Factor Xa Inhibitors
Applied to Man 290
D. Conclusions 292
References 293
CHAPTER 16
Inhibitors of Papain Like Cysteine Peptidases in Cancer
R. Shridhar, B.F. Sloane, and D. Keppler. With 2 Figures 301
A. Introduction 301
B. General Overview 301
I. Cysteine Peptidases 301
II. Cystatin Super family 302
XXVI Contents
1. Family 1 (Stefins) 302
2. Family 2 (Cystatins) 304
3. Family 3 (Kininogens) 306
4. Families 4,5,6 (Fetuins, Cystatin Related Proteins,
Histidine Rich Glycoproteins) 306
III. Mechanism of Inhibition 307
C. Cystatins in Cancer 310
I. Inhibitory Activity 310
II. Stefins A and B 311
III. Cystatins C and E/M 312
IV. Synthetic Inhibitors 314
D. Potential Transcriptional Regulation 316
I. Stefins A and B 317
II. Cystatin C 319
III. Links to Cancer Progression 319
E. Perspectives: Therapeutic Implications 320
References 321
CHAPTER 17
Caspases and Their Natural Inhibitors as Therapeutic Targets
for Regulating Apoptosis
Q.L. Deveraux, J.C. Reed, and G.S. Salvesen. With 3 Figures 329
A. Apoptosis 329
B. Apoptosis Is Mediated by Caspase 329
C. Lessons Learned from Natural Caspase Inhibitors 330
D. Sturctural Characteristics of the IAPs 332
E. Biology of the Human IAPs 333
F. IAPs as Therapeutic Targets 334
G. Potential for Caspase Inhibitor Therapy 335
H. Conclusions 336
References 337
CHAPTER 18
Proteasome and Apoptosis
K. Tanaka and H. Kawahara. With 2 Figures 341
A. Introduction 341
B. The Ub System 341
I. The Ub Ligating Pathway 341
II. Ubiquitination and Cell Cycle 343
III. Deubiquitinating Enzymes and Cell Proliferation 344
C. The Proteasome: a Protein Killing Machine 345
] Contents XXVII
D. Regulatory Control of Ub and the Proteasome in Apoptosis .... 346
E. Proteasome Inhibitors Help Elucidate the Biological Roles
of the Proteasome in the Apoptotic Pathway 348
F. The Ub Proteasome System and Cancer Therapy 353
G. Perspectives 354
References 355
CHAPTER 19
Proteolytic Processing of the Amyloid Precursor Protein of
Alzheimer s Disease
S.F. Lichtenthaler, C.L. Masters, and K. Beyreuther.
With 1 Figure 359
A. Introduction 359
B. Molecular Biology of AD 360
I. The Amyloid Precursor Protein 360
II. Overview of the Proteolytic Processing of APP 360
C. Description of the Proteolytic Activities Cleaving APP 362
I. a Secretase 363
II. j3 Secretase 365
III. ^Secretase 366
IV. 5 Secretase 369
D. Therapeutic Potential of the APP Secretases 369
References 370
CHAPTER 20
Presenilins and /} Amyloid Precursor Protein Proteolytically Processed
Proteins Involved in the Generation of Alzheimer s Amyloid fi Peptide
C. Haass. With 5 Figures 375
A. Introduction 375
B. Proteolytic Generation of the Amyloid /? Peptide 375
I. Endosomal/Lysosomal Processing Generates
Amyloidogenic Precursors 376
II. A/3 Is Produced by a Physiological Processing Pathway .... 377
HI. FAD Linked Mutations in the J3APP Gene Affect Aj3
Generation 377
C. Role of Mutant Presenilins in Amyloid Generation 378
I. Structure and Topology of PS Proteins 379
D. Conventional Proteolytic Processing of PS Proteins 381
I. Identification of the Cleavage Site 381
II. Regulation of Fragment Formation 382
III. Effects of PS Mutations on Fragment Formation 382
I
XXVIII Contents
E. Proteolytic Degradation of PSs 384
I. PS Holoproteins Are Degraded by the Proteasome 384
II. PSs Are Death Substrates for Caspases 384
III. A Heterodimeric PS Complex Appears to Be Required for
PS Stability and A/342 Generation 386
F. Evidence That PSs Activate the y Secretase Cleavage 388
G. PSs: New Targets for Anti Amyloidogenic Drugs? 390
References 390
Appendix 397
Subject Index 403
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| genre | (DE-588)4143413-4 Aufsatzsammlung gnd-content |
| genre_facet | Aufsatzsammlung |
| id | DE-604.BV012770374 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T18:33:21Z |
| institution | BVB |
| isbn | 3540661182 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-008684217 |
| oclc_num | 468542287 |
| open_access_boolean | |
| owner | DE-355 DE-BY-UBR DE-19 DE-BY-UBM DE-12 DE-188 DE-578 |
| owner_facet | DE-355 DE-BY-UBR DE-19 DE-BY-UBM DE-12 DE-188 DE-578 |
| physical | XXVIII, 410 S. Ill., graph. Darst. |
| publishDate | 2000 |
| publishDateSearch | 2000 |
| publishDateSort | 2000 |
| publisher | Springer |
| record_format | marc |
| series | Handbook of experimental pharmacology |
| series2 | Handbook of experimental pharmacology |
| spelling | Proteases as targets for therapy [with 16 tables] contributors S. S. Abdel-Meguid ... Ed. Klaus von der Helm ... Berlin [u.a.] Springer 2000 XXVIII, 410 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Handbook of experimental pharmacology 140 Protease Inhibitors cabt Antipeptidases - Emploi en thérapeutique ram Inhibiteurs de protéase du VIH - usage thérapeutique Inhibiteurs de protéases - usage thérapeutique Peptidases - Aspect médical ram Geschichte (DE-588)4020517-4 gnd rswk-swf Pharmakologie (DE-588)4045687-0 gnd rswk-swf Proteaseinhibitor (DE-588)4130450-0 gnd rswk-swf Proteasen (DE-588)4047521-9 gnd rswk-swf HIV-Infektion (DE-588)4203852-2 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Proteasen (DE-588)4047521-9 s Pharmakologie (DE-588)4045687-0 s DE-604 HIV-Infektion (DE-588)4203852-2 s Proteaseinhibitor (DE-588)4130450-0 s Geschichte (DE-588)4020517-4 s Helm, Klaus von der Sonstige oth Abdel-Meguid, Sherin S. Sonstige oth Handbook of experimental pharmacology 140 (DE-604)BV002390716 140 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=008684217&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Proteases as targets for therapy [with 16 tables] Handbook of experimental pharmacology Protease Inhibitors cabt Antipeptidases - Emploi en thérapeutique ram Inhibiteurs de protéase du VIH - usage thérapeutique Inhibiteurs de protéases - usage thérapeutique Peptidases - Aspect médical ram Geschichte (DE-588)4020517-4 gnd Pharmakologie (DE-588)4045687-0 gnd Proteaseinhibitor (DE-588)4130450-0 gnd Proteasen (DE-588)4047521-9 gnd HIV-Infektion (DE-588)4203852-2 gnd |
| subject_GND | (DE-588)4020517-4 (DE-588)4045687-0 (DE-588)4130450-0 (DE-588)4047521-9 (DE-588)4203852-2 (DE-588)4143413-4 |
| title | Proteases as targets for therapy [with 16 tables] |
| title_auth | Proteases as targets for therapy [with 16 tables] |
| title_exact_search | Proteases as targets for therapy [with 16 tables] |
| title_full | Proteases as targets for therapy [with 16 tables] contributors S. S. Abdel-Meguid ... Ed. Klaus von der Helm ... |
| title_fullStr | Proteases as targets for therapy [with 16 tables] contributors S. S. Abdel-Meguid ... Ed. Klaus von der Helm ... |
| title_full_unstemmed | Proteases as targets for therapy [with 16 tables] contributors S. S. Abdel-Meguid ... Ed. Klaus von der Helm ... |
| title_short | Proteases as targets for therapy |
| title_sort | proteases as targets for therapy with 16 tables |
| title_sub | [with 16 tables] |
| topic | Protease Inhibitors cabt Antipeptidases - Emploi en thérapeutique ram Inhibiteurs de protéase du VIH - usage thérapeutique Inhibiteurs de protéases - usage thérapeutique Peptidases - Aspect médical ram Geschichte (DE-588)4020517-4 gnd Pharmakologie (DE-588)4045687-0 gnd Proteaseinhibitor (DE-588)4130450-0 gnd Proteasen (DE-588)4047521-9 gnd HIV-Infektion (DE-588)4203852-2 gnd |
| topic_facet | Protease Inhibitors Antipeptidases - Emploi en thérapeutique Inhibiteurs de protéase du VIH - usage thérapeutique Inhibiteurs de protéases - usage thérapeutique Peptidases - Aspect médical Geschichte Pharmakologie Proteaseinhibitor Proteasen HIV-Infektion Aufsatzsammlung |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=008684217&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| volume_link | (DE-604)BV002390716 |
| work_keys_str_mv | AT helmklausvonder proteasesastargetsfortherapywith16tables AT abdelmeguidsherins proteasesastargetsfortherapywith16tables |