Antisense research and application: [with 42 tables]
Gespeichert in:
| Format: | Buch |
|---|---|
| Sprache: | English |
| Veröffentlicht: |
Berlin [u.a.]
Springer
1998
|
| Schriftenreihe: | Handbook of experimental pharmacology
131 |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XXVI, 630 S. Ill., graph. Darst. |
| ISBN: | 3540638334 |
Internformat
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| 245 | 1 | 0 | |a Antisense research and application |b [with 42 tables] |c contributors S. Agrawal ... Ed. Stanley T. Crooke |
| 264 | 1 | |a Berlin [u.a.] |b Springer |c 1998 | |
| 300 | |a XXVI, 630 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 1 | |a Handbook of experimental pharmacology |v 131 | |
| 650 | 7 | |a Antisense Elements [Genetics] |2 cabt | |
| 650 | 7 | |a Pharmacology |2 cabt | |
| 650 | 7 | |a Antisense-ketens |2 gtt | |
| 650 | 7 | |a Farmacotherapie |2 gtt | |
| 650 | 7 | |a Genexpressie |2 gtt | |
| 650 | 4 | |a Antisense Elements (Genetics) |x pharmacology | |
| 650 | 4 | |a Antisense Elements (Genetics) |x therapeutic use | |
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Datensatz im Suchindex
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| adam_text | Contents
CHAPTER 1
Basic Principles of Antisense Therapeutics
S.T. Crooke. With 3 Figures 1
A. Introduction 1
B. Proof of Mechanism 1
I. Factors that May Influence Experimental
Interpretations 1
1. Oligonucleotide Purity 1
2. Oligonucleotide Structure 2
3. RNA Structure 2
4. Variations in In Vitro Cellular Uptake and
Distribution 2
5. The Binding to and Effects of Binding to
Nonnucleic Acid Targets 3
6. Terminating Mechanisms 3
7. Effects of Control Oligonucleotides 4
8. Kinetics of Effects 4
II. Recommendations 4
1. Positive Demonstration of Antisense
Mechanism and Specificity 4
C. Molecular Mechanisms of Antisense Drugs 5
I. Occupancy Only Mediated Mechanisms 5
1. Inhibition of Splicing 5
2. Translational Arrest 6
3. Disruption of Necessary RNA Structure 7
II. Occupancy Activated Destabilization 8
1. 5 Capping 8
2. Inhibition of 3 Polyadenylation 9
III. Other Mechanisms 9
IV. Activation of RNase H 10
V. Activation of Double Strand RNase 12
D. Characteristics of Phosphorothioate Oligodeoxynucleotides ... 12
I. Introduction 12
II. Hybridization 13
XII Contents
III. Interactions with Proteins 13
IV. Pharmacokinetic Properties 15
1. Nuclease Stability 15
2. In Vitro Cellular Uptake 16
3. In Vivo Pharmacokinetics 16
V. Pharmacological Properties 20
1. Molecular Pharmacology 20
2. In Vivo Pharmacological Activities 22
VI. Toxicological Properties 26
1. In Vitro 26
2. Genotoxicity 27
3. In Vivo 28
VII. Therapeutic Index 29
VIII. Conclusions 30
E. The Medicinal Chemistry of Oligonucleotides 31
I. Introduction 31
II. Heterocycle Modifications 32
1. Pyrimidine Modifications 32
2. Purine Modifications 33
3. Oligonucleotide Conjugates 33
a) Nuclease Stability 34
b) Enhanced Cellular Uptake 34
c) RNA Cleaving Groups 35
d) In Vivo Effects 35
4. Sugar Modifications 36
5. Backbone Modifications 37
III. Conclusions 38
References 38
CHAPTER 2
Antisense Medicinal Chemistry
D. Cook. With 11 Figures 51
A. Introduction 51
B. Scope of the Review 51
C. Phosphorothioates as Antisense Drug Candidates 52
D. Phosphorothioate Limitations 53
I. Pharmacodynamic Limitations 53
II. Pharmacokinetic Limitations 54
III. Toxicological Limitations 54
E. Types of Oligonucleotide Modifications 55
F. Drug Properties of Antisense Oligonucleotides that May Be
Altered by Chemical Modifications 55
Contents XIII
G. Why Is it Important to Continue to Design and Synthesize
Antisense Oligonucleotides with Increased Affinity for
Target RNA and with Greater Resistance to Nucleolytic
Degradation? 56
H. What Are the Standards for Binding Affinity,
Nuclease Resistance, and Other Properties Recently Achieved
by Structure Property/Activity Relationship Studies
of Oligonucleotides? 57
I. Summary of Key Oligonucleotide Modifications 59
I. Heterocycles (Nucleobases) 59
1. 5 Position Pyrimidine and Tricyclic Cytidine
Modified Oligonucleotides 59
2. yV2 Purine Modified Oligonucleotides 61
3. 7 Deaza Modified Oligonucleotides 63
4. Additional Advantages of Heterocycle Modified
Oligonucleotides 64
5. Toxicity Liability of Heterocyclic Modifications 65
II. Carbohydrate Modified Oligonucleotides 66
1. Basis for Design 67
2. 4 Modified Oligonucleotides 67
3. Sugar Conformationally Restricted
Oligonucleotides 67
4. Morpholino Diamidate Modified Oligomers 69
5. 2 Modified Oligonucleotides 69
a) Structure Property/Activity Relationship
Studies 69
a) Binding Properties of 2 O Modified
Oligonucleotides 70
P) Stability of 2 O Modified Oligonucleotides 71
b) Modes of Action of 2 Modified
Oligonucleotides 72
a) Chimera 2 0 Modified Oligonucleotides
RNase H Dependent Mode of Action (Gapmer
Technology) 72
p) 2 O Modified Oligonucleotides with an RNase
H Independent Mode of Action 76
c) Selected, Interesting Antisense Results With 2 O
Modified Oligonucleotides in Gapmer Motifs 77
d) Pharmacokinetic Properties of 2 Modified
Oligonucleotides 78
e) Toxicity Implications of 2 Modified
Oligonucleotides 80
f) Summary of 2 Sugar Modified
Oligonucleotides 81
XIV Contents
III. Backbone or Linkage Modified Oligonucleotides 82
1. MMI and Amide 3 Modified
Oligonucleosides/tides 82
2. 3 Amidate Modified Oligonucleotides 84
3. 3 Thioformacetal and Formacetal Modified
Oligomers 85
4. 2 Modified tfp Me Phosphonates 85
5. Peptide Nucleic Acid 85
6. General Observations About Backbone
Research 86
IV. Oligonucleotide Pendants (Conjugates) 87
J. Conclusions 90
References 92
CHAPTER 3
In Vitro Cellular Uptake, Distribution, and Metabolism of
Oligonucleotides
R.M. Crooke. With 14 Figures 103
A. Introduction 103
B. Stability in the Extracellular Milieu 104
I. Phosphodiester Oligonucleotides 104
II. Methylphosphonate Oligonucleotides 105
III. Phosphorothioate Oligonucleotides 106
C. In Vitro Uptake, Intracellular Distribution, and Efflux 106
I. Phosphodiester Oligonucleotides ^.. 106
2. Intracellular Distribution 109
3. Efflux 110
II. Methylphosphonate Oligonucleotides Ill
1. Uptake Ill
2. Intracellular Distribution 112
3. Efflux 112
III. Phosphorothioate Oligonucleotides 113
1. Uptake 113
2. Intracellular Distribution 116
3. Efflux 119
D. Intracellular Stability 120
I. Phosphodiester Oligonucleotides 101
II. Methylphosphonate Oligonucleotides 122
III. Phosphorothioate Oligonucleotides 122
E. Uptake Enhancement Methods 128
F. Conclusions 130
References 133
I Contents XV
CHAPTER 4
I Pharmacokinetic Properties of Phosphorothioates in Animals
I Absorption, Distribution, Metabolism and Elimination
| P.L. Nicklin, SJ. Craig, and J.A. Phillips. With 12 Figures 141
j A. Introduction 141
I. Phosphorothioate Modification 143
| II. Oligonucleotide Detection and Analysis 144
B. Distribution 145
¦j I. Blood Kinetics 145
1 II. Tissue Distribution 147
I III. Cellular Uptake In Vivo 147
j IV. Dose Dependence 150
V. Sequence Dependence 150
VI. Multiple Dosing 153
C. Metabolism 153
I. Plasma 155
II. Tissues 155
D. Elimination 159
E. Absorption 161
I. Parenteral Administration 162
II. Local Administration 164
III. Non parenteral Administration 164
F. Conclusion 165
References 166
CHAPTER 5
Toxicity of Oligodeoxynucleotide Therapeutic Agents
A.A. Levin, D.K. Monteith, J.M. Leeds, P.L. Nicklin, R.S. Geary,
M. Butler, M.V. Templin, and S.P. Henry. With 13 Figures 169
A. Introduction 169
B. Pharmacokinetics and Metabolism 173
C. Toxicity of Phosphorothioate Oligodeoxynucleotides 179
I. Genetic Toxicity 179
II. Acute Toxicities 179
1. Complement Activation 180
a) Effects of Oligodeoxynucleotide Chemistries 186
2. Hemostasis 187
a) Effects of Oligodeoxynucleotide Chemistries 191
III. Toxicologic Effects Associated with
Chronic Exposure 192
1. Immune Stimulation 192
a) Effects of Oligodeoxynucleotide Chemistries 199
XVI Contents
2. Hepatic Effects of Oligodeoxynucleotide
Treatment 200
3. Renal Effects of Oligodeoxynucleotide Treatment ... 202
4. Hematopoiesis 205
IV. Reproductive Effects of Antisense
Oligodeoxynucleotides 205
V. Ocular Toxicity of Antisense Therapeutic Agents 206
1. Ocular Pharmacokinetics 207
2. Ocular Toxicity Profile 208
References 210
CHAPTER 6
Pharmacokinetic Properties of Phosphorothioate Oligonucleotides
in Humans ;
J.M. Leeds and R.S. Geary. With 4 Figures 217
A. Introduction 217
B. Human Pharmacokinetics 218
I. Absorption 219
II. Plasma Pharmacokinetics 220
1. Peak Plasma Concentrations 220
2. Calculated Parameters 221
III. Metabolism 223
IV. Elimination 228
C. Pharmodynamics 230
References 231
CHAPTER 7
Safety and Tolerance of Phosphorothioates in Humans
P.J. Schechter and R.R. Martin. With 3 Figures 233
A. Introduction 233
B. Cardiovascular Safety 233
C. Hematological Safety 234
I. Coagulation 234
II. Platelets 235
III. Red Blood Cells 236
D. Complement Activation 237
E. Specific Organ Toxicity 237
F. Conclusion 239
References 239
CHAPTER 8
Immune Stimulation by Oligonucleotides
A.M. Krieg 243
Contents XVII
A. Sequence Independent Immune Effects of the DNA
Backbone 243
B. Sequence Specific Immune Effects of CpG
Motifs in Oligodeoxynucleotides 245
I. Immune Activation by Bacterial DNA and the
Identification of Stimulatory Palindromes 245
II. Immune Activation by Antisense and Control
I Oligodeoxynucleotides 246
! III. Discovery of Immune Activation by CpG Motifs 247
I IV. Immune Effects of CpG Motifs 250
I 1. Mitogenic and Anti apoptotic Effects of
Oligodeoxynucleotides 250
a) Virtually All B Cells Can Respond to the Mitogenic
Effects of CpG Oligodeoxynucleotides 250
b) CpG DNA Blocks B Cell Apoptosis 251
c) Induction of B Cell Cytokine and Ig Secretion by
CpG DNA 251
2. Induction of Monocyte Cytokine Secretion by
CpG DNA 252
3. Induction of Natural Killer Interferon g Secretion
and Lytic Activity by CpG DNA 253
V. Role of the Phosphorothioate Backbone in the Immune
Effects of CpG Oligodeoxynucleotides 254
VI. Mechanism of Leukocyte Activation by CpG
Oligodeoxynucleotides 254
VII. Teleologic Significance of Immune Activation by CpG
Motifs in DNA 256
C. Sequence Specific Immune Effects of Poly(G) Motifs in
Oligodeoxynucleotides 258
References 258
CHAPTER 9
Pharmacological Inhibition of Dopaminergic and Other
Neurotransmitter Receptors Using Antisense Oligodeoxynucleotides
G. Davidkova and B. Weiss. With 5 Figures 263
A. Introduction 263
B. Advantages of Antisense Oligodeoxynucleotides over
Traditional Pharmacological Antagonists 264
C. Factors to Consider in the Development of Antisense
Oligodeoxynucleotides Targeted to Neurotransmitter
Receptors 266
I. Structure of Antisense Oligodeoxynucleotides: Optimal
Recognition Site on the Targeted Transcript and
XVIII Contents
Oligodeoxynucleotide Length and Chemical
Structure 266
II. In Vitro and In Vivo Substrates for Studying Antisense
Oligodeoxynucleotides 272
III. Delivery Systems 273
D. Uptake and Distribution of Antisense
Oligodeoxynucleotides 273
E. Mechanism of Action of Antisense Oligodeoxynucleotides .... 276
I. Mechanisms of Inhibition of Gene Expression 276
II. Appropriate Controls to Determine the Specificity of
Antisense Effects 277
III. Functional, Biochemical, and Molecular Consequences
of Antisense Inhibition 277
IV. Antisense Oligodeoxynucleotides Inhibit a Pool of
Functional Neurotransmitter Receptors 278
F. In Vitro and In Vivo Effects of Antisense
Oligodeoxynucleotides Targeted to the Transcripts Encoding
Neurotransmitter Receptors 281
I. Acetylcholine Receptors 281
II. Adrenergic Receptors 282
III. Dopamine Receptors 283
1. In Vivo Models for Studying the Effects of Dopamine
Receptor Antisense Oligodeoxynucleotides 285
2. Design and Synthesis of Antisense
Oligodeoxynucleotides Targeted to the Dopamine
Receptor Intended for In Vivo Use 286
3. D, Dopamine Receptor Antisense 286
a) In Vivo Studies 286
b) In Vitro Studies 289
4. D2 Dopamine Receptor Antisense 290
a) In Vivo Studies 290
b) In Vitro Studies 293
5. D3 Dopamine Receptor Antisense 294
IV. GABA Receptors 295
V. NMDA Receptors 298
VI. Serotonin Receptors 299
G. Future Directions: Comparison Between the Properties of
Antisense Oligodeoxynucleotides and Antisense RNA
Produced by Mammalian Expression Vectors 300
H. Conclusions 301
References 302
CHAPTER 10
Pharmacological Effects of Antisense Oligonucleotide Inhibition of
Immediate Early Response Genes in the CNS
B.J. Chiasson, M.O. Hebb, and H.A. Robertson. With 3 Figures 309
Contents XIX
A. Introduction 309
B. Some Correlative Studies Suggesting a Role of Immediate
Early Genes in Brain Function 309
C. Immediate Early Genes and Stimulus Transcription
Coupling 311
I. A Model for Change 311
II. The Origin of Immediate Early Genes 312
III. The Immediate Early Gene as an Inducible
Transcription Factor 312
IV. Immediate Early Gene Transcription Factors and Their
Targets 313
D. Studies Using Antisense Oligodeoxynucleotides in the CNS ... 315
I. The Induction of c fos in the Striatum 315
II. Knockdown of Amphetamine Induced c fos Using
Antisense Oligodeoxynucleotides: Studies of the Basal
Ganglia Function 317
III. The Amygdala and Gene Expression 322
IV. Exploring Alternative Modifications to
Oligonucleotides 328
V. Reconciling Differences 330
VI. Other Studies Using Antisense Oligonucleotides in
Nervous Tissue 331
E. Neural Plasticity and the Role of c fos as Demonstrated
by Antisense Technology 332
References 333
CHAPTER 11
Inhibition of G Proteins by Antisense Drugs
F. Kalkbrenner, B. Wittig, and G. Schultz. With 4 Figures 341
A. Introduction 341
B. Antisense Approaches to Study Signal Transduction
Pathways 344
C. Inhibition of G Protein Functions by Antisense RNA and
Genomic Knockout 345
D. Inhibition of G Protein Functions by Antisense
Oligodeoxynucleotides in Cell Culture 350
I. Nuclear Microinjection of G Protein Antisense
Oligodeoxynucleotides 350
II. Signal Transduction Pathways Leading to G Protein
Mediated Inhibition of Voltage Gated Calcium
Channels in Neuroendocrine Cells 352
III. Signal Transduction Pathways Leading to a G Protein
Mediated Increase in the Intracellular Calcium
Concentration 354
XX Contents
IV. Specificity of Antisense Effects 356
V. Application of G Protein Antisense
Oligodeoxynucleotides Through the Patch
Clamp Pipette 357
VI. Application of G Protein Antisense
Oligodeoxynucleotides by Adding to the Cell
Culture Medium 358
E. Inhibition of G Protein Functions by Antisense
Oligodeoxynucleotides in Animals 360
F. Perspectives 363
References 364
CHAPTER 12
Use of Antisense Oligonucleotides to Modify Inflammatory Processes
C.F. Bennett and T.P. Condon. With 1 Figure 371
A. Introduction 371
B. Cell Adhesion Molecules 373
I. Intercellular Adhesion Molecule 1 376
1. Pharmacology of ICAM 1 Antisense
Oligonucleotides 377
a) Proof of Mechanism 377
b) Human Xenografts 378
c) Rodent Allografts 379
d) Colitis 381
e) Renal Ischemia 382
2. Toxicology of ICAM 1 Antisense Oligonucleotides ... 382
3. Clinical Studies with ISIS 2302 383
4. Second and Third Generation Chemistry 383
II. Other Endothelial Cell Leukocyte Adhesion
Molecules 384
C. Nuclear Factor kB 385
D. Interleukin 1 Receptors 386
E. Conclusions 386
References 387
CHAPTER 13
Antisense Oligonucleotides and Their Anticancer Activities
D. Fabbko, M. Muller, and T. Geiger. With 6 Figures 395
A. Potential Cancer Targets for Pharmaceutical Intervention 395
B. Antisense Based Approaches and Cancer 396
C. Antisense Targets Related to Solid Tumors 396
I. ras and raf 396
J
I
Contents XXI
II. Growth Factors and Growth Factor Receptors 404
III. Proteases 405
IV. Multidrug Resistance 405
V. Miscellaneous 406
D. Antisense Targets Related to Hematological Malignancies .... 407
I. Chronic Myelogenous Leukemia and bcr abl 407
II. myc, myb, and bcl 2 408
E. Protein Kinase C a and raf as Cancer Targets for Antisense ... 408
I. In Vivo Activity of Phosphorothioate Antisense
Oligonucleotide Targeting Protein Kinase
C a and c raf 408
II. In Vivo Activity of Modified and Formulated Antisense
Oligonucleotides Targeting c raf 410
1. 2 Methoxy ethoxy Modified Oligonucleotides 410
2. Antitumor Activity of CGP 69846A in Stealth
Liposomes 411
3. Antitumor Activity of CGP 69846A with Dextran
Sulfate or as Cholesterol Conjugates of CGP
69846A 411
F. Concluding Remarks 414
References 417
CHAPTER 14
Pharmacological Activity of Antisense Oligonucleotides in Animal
Models of Disease
B.P. Monia and N.M. Dean 427
A. Introduction 427
B. Vascular System 427
I. Restenosis 427
II. Atherosclerosis 432
III. Hypertension 434
IV. Ocular Neovascularization 435
C. Skin 436
D. Peripheral Organs 437
I. Liver 438
II. Kidney 439
III. Lung 439
E. Conclusions and Future Directions 440
References 440
CHAPTER 15
Clincial Antiviral Activities
S.L. Hutcherson. With 2 Figures 445
XXII Contents
A. Introduction 445
B. Antisense Oligonucleotide Antiviral Pharmacology 447
C. Pharmacokinetic Assessment Strategies 448
D. Toxicology for Antisense Oligonucleotide Antivirals 449
E. Chemical Synthesis Scale Up and Chemical Development 450
F. Clinical Research of Antisense Oligonucleotides 450
G. Future Antisense Antiviral Development 455
References 456
CHAPTER 16
Antisense Oligonucleotides to Protein Kinase C aand C ra/Kinase:
Rationale and Clinical Experience in Patients with Solid Tumors
F.A. Dorr and D.L. Kisner 463
A. Introduction 463
B. Rationale for the Development of an Inhibitor of Protein
Kinase C (ISIS 3521) 464
C. Rationale for the Development of an Inhibitor of C raf
Kinase (ISIS 5132) 465
D. Preclinical Toxicology and Pharmacokinetics 466
E. Status of Clinical Development 468
I. ISIS 3521 468
1. Clinical Study 1 468
2. Clinical Study 2 469
II. ISIS 5132 471
1. Clinical Study 1 471
2. Clinical Study 2 472
F. Future Clinical Development 473
References 474
CHAPTER 17
Nucleic Acid Therapeutics for Human Leukemia: Development and
Early Clinical Experience with Oligodeoxynucleotides Directed
at c myb
A.M. Gewirtz. With 10 Figures 477
A. Introduction 477
B. c myb Proto oncogene 477
I. Targeting the c myb Gene 479
II. In Vitro Experience in the Hematopoietic
Cell System 479
1. Role of c myfo Encoded Protein in Normal Human
Hematopoiesis 479
Contents XXIII
2. Myb Protein Requirement for Leukemic
Hematopoiesis 480
3. Differential Reliance of Normal and Leukemic
Progenitor Cells on c myb Function 483
4. Use of c myb Oligodeoxynucleotides as Bone
Marrow Purging Agents 484
5. Efficacy of c myb Oligodeoxynucleotides In Vivo:
Development of Animal Models 485
III. Why Downregulating myb Kills Leukemic Cells
Preferentially: A Hypothesis 487
IV. Pharmacodynamic Studies with an myb Targeted
Oligodeoxynucleotide 488
C. Use of Antisense Oligonucleotides in a Clinical Setting 491
D. Future Outlook 492
E. Conclusions 494
References 495
CHAPTER 18
Properties of ISIS 2302, an Inhibitor of Intercellular Adhesion
Molecule l, Humans
W.R. Shanahan Jr. With 8 Figures 499
A. Introduction 499
B. Phase I Intravenous Trial 501
I. Methods and Material 501
II. Results 502
1. Safety 502
2. Pharmacokinetics 504
III. Discussion 510
C. Phase Ha Trials 513
I. Crohn s Disease 514
II. Rheumatoid Arthritis 517
III. Ulcerative Colitis 517
IV. Psoriasis 517
V. Renal Transplantation 518
D. Exploration of Subcutaneous Dosing 519
E. Future Plans 523
References 521
CHAPTER 19
Pharmacokinetics and Unavailability of Antisense Oligonucleotides
Following Oral and Colorectal Administrations in
Experimental Animals
S. Agrawal and R. Zhang. With 10 Figures 525
XXIV Contents
A. Introduction 525
B. Oral Administration 526
I. Experimental Design 526
1. Synthesis of Unlabeled and [3SS] Labeled
Oligonucleotides 526
2. Animals and Drug Administration 526
3. Absolute Bioavailability 527
4. Sample Preparation and Total Radioactivity
Measurements 528
5. Gel Electrophoresis 528
6. High Performance Liquid Chromatography
Analysis 528
II. Results and Discussion 529
1. Phosphorothioate Oligonucleotide 529
2. Mixed Backbone Oligonucleotide 1 529
3. Mixed Backbone Oligonucleotide 2 532
4. General Discussion 533
C. Colorectal Administration 534
I. Special Considerations in Experimental Design 534
II. Results and Discussion 535
1. Mixed Backbone Oligonucleotide 1 535
2. Phosphorothioate Oligonucleotide and End Modified
Mixed Backbone Oligonucleotide 2 536
3. General Discussion 538
D. Conclusions 540
References 541
CHAPTER 20
Antisense Properties of Peptide Nucleic Acid
P.E. Nielsen. With 7 Figures 545
A. Introduction 545
B. Chemistry 545
C. Hybridization Properties 545
D. Structure of Peptide Nucleic Acid Complexes 547
E. Antisense Activity (Mechanism of Action) 548
F. Cellular Biology 549
G. Peptide Nucleic Acid Derivatives (Structure Activity
Relationships) 549
H. Peptide Nucleic Acid DNA Chimeras 553
I. Antigene Activity 555
J. Future Prospects 557
References 557
Contents XXV
CHAPTER 21
Triple Helix Strategies and Progress
T. Akiyama and M. Hogan. With 2 Figures 561
A. Introduction 561
B. Discovery of the Triple Helix Structure 561
C. Detailed Structure of the Triple Helix 562
I. Nuclear Magnetic Resonance Studies 564
1. Hydrogen Bonding 564
2. Base Orientation 564
II. Other Methods to Investigate Triple Helix Structure ... 565
1. Infrared Spectroscopy 565
2. Phase Sensitive Electrophoresis 565
3. Electron Microscopy 565
4. X ray Crystallography 566
5. Molecular Dynamics Simulation 566
D. Stability of the Triple Helix 566
I. Thermodynamic Analysis by Spectroscopic and
Calorimetric Methods 566
II. Thermodynamic Analysis by Biochemical Methods 568
III. Factors Influencing the Stability of the Triple Helix 569
1. Mismatching at Inversion Sites 569
2. Ionic Strength 570
3. Effect of pH 571
IV. Kinetics of Triple Helix Formation 571
E. Nucleoside Modification to Improve Triple Helix Stability 571
I. Modified Nucleoside to Overcome pH Dependency
of the Parallel Triple Helix 571
1. Cytidine Derivatives 572
2. Adenosine Derivatives 572
3. Guanosine Derivatives 573
II. New Nucleosides to Recognize Invasion Sites 573
III. Modification to Overcome Alkali Metal Mediated
Inhibition of Antiparallel Triple Helix Formation 573
F. Triple Helix Binding Ligands 574
I. The Triple Helix as a Target for Small Molecule
Recognition 574
II. Ethidium Bromide 574
III. Benzopyridoindole Derivatives 575
IV. Naphtyl Quinoline Derivative 575
V. Other Intercalators 575
VI. Minor Groove Binding Ligands 576
VII. Polyamines and Basic Oligopeptides 576
G. Backbone Modification and Strand Switching 577
I. DNA and RNA Backbone 577
XXVI Contents
II. Chemical Modification of Backbones 577
III. Alternate Strand Recognition and Minor Helix
Groove Bridging 578
H. Conjugation of Small Compounds Enhance Triple
Helix Stability 579
I. Conjugation of Intercalators 579
II. Conjugation of Other Small Compounds 580
I. Inhibition of Transcription by Triple Helix
Technology 580
I. Prospects for Triple Helix Mediated Gene
Regulation 580
II. Inhibition of Transcription Factor Binding by Triple
Helix Formation 581
III. Inhibition of Transcription by Triple Helix
Formation in a Cell free System 581
IV. Change of Nucleosome Positioning by Triple
Helix Formation 584
V. Transcription Inhibition by Triple Helix Formation
in Cell 584
J. Other Pharmaceutically Interesting Effects of Triple Helix
Formation 587
I. Inhibition of DNA Replication 587
II. Inhibition of HIV Integration by Triple Helix 587
K. Targeting Single Stranded DNA or RNA by Triple
Helix Formation 588
L. DNA Modification Mediated by TFO Binding 589
I. Sequence Specific DNA Cleavage 589
II. Sequence Specific Alkylation 589
III. Single Site Enzymatic Cleavage 589
IV. Photo Induced Cross Linking 590
V. Targeted Mutagenesis by a Psoralen Linked TFO 590
M. Recent Topics and Prospects 591
I. Artificial DNA Bending by Triple Helix Formation 591
N. Conclusion 592
References 593
Subject Index 611
|
| any_adam_object | 1 |
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| callnumber-first | Q - Science |
| callnumber-label | QP905 |
| callnumber-raw | QP905 RM666.A564 |
| callnumber-search | QP905 RM666.A564 |
| callnumber-sort | QP 3905 |
| callnumber-subject | QP - Physiology |
| classification_rvk | XI 1701 |
| ctrlnum | (OCoLC)37993314 (DE-599)BVBBV011801520 |
| dewey-full | 615/.1 615/.31 |
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| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615/.1 615/.31 |
| dewey-search | 615/.1 615/.31 |
| dewey-sort | 3615 11 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| format | Book |
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| genre | (DE-588)4143413-4 Aufsatzsammlung gnd-content |
| genre_facet | Aufsatzsammlung |
| id | DE-604.BV011801520 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T18:15:59Z |
| institution | BVB |
| isbn | 3540638334 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-007968111 |
| oclc_num | 37993314 |
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| owner_facet | DE-355 DE-BY-UBR DE-19 DE-BY-UBM DE-12 DE-20 DE-188 DE-578 |
| physical | XXVI, 630 S. Ill., graph. Darst. |
| publishDate | 1998 |
| publishDateSearch | 1998 |
| publishDateSort | 1998 |
| publisher | Springer |
| record_format | marc |
| series | Handbook of experimental pharmacology |
| series2 | Handbook of experimental pharmacology |
| spelling | Antisense research and application [with 42 tables] contributors S. Agrawal ... Ed. Stanley T. Crooke Berlin [u.a.] Springer 1998 XXVI, 630 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Handbook of experimental pharmacology 131 Antisense Elements [Genetics] cabt Pharmacology cabt Antisense-ketens gtt Farmacotherapie gtt Genexpressie gtt Antisense Elements (Genetics) pharmacology Antisense Elements (Genetics) therapeutic use Antisense nucleic acids Therapeutic use Antisense-Oligonucleotide (DE-588)4371006-2 gnd rswk-swf Pharmakologie (DE-588)4045687-0 gnd rswk-swf Antisense-Nucleinsäuren (DE-588)4282992-6 gnd rswk-swf Heilmittel (DE-588)4024069-1 gnd rswk-swf (DE-588)4143413-4 Aufsatzsammlung gnd-content Antisense-Oligonucleotide (DE-588)4371006-2 s Heilmittel (DE-588)4024069-1 s DE-604 Antisense-Nucleinsäuren (DE-588)4282992-6 s Pharmakologie (DE-588)4045687-0 s Crooke, Stanley T. 1945- Sonstige (DE-588)115845291 oth Agrawal, Sudhir Sonstige oth Handbook of experimental pharmacology 131 (DE-604)BV002390716 131 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=007968111&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Antisense research and application [with 42 tables] Handbook of experimental pharmacology Antisense Elements [Genetics] cabt Pharmacology cabt Antisense-ketens gtt Farmacotherapie gtt Genexpressie gtt Antisense Elements (Genetics) pharmacology Antisense Elements (Genetics) therapeutic use Antisense nucleic acids Therapeutic use Antisense-Oligonucleotide (DE-588)4371006-2 gnd Pharmakologie (DE-588)4045687-0 gnd Antisense-Nucleinsäuren (DE-588)4282992-6 gnd Heilmittel (DE-588)4024069-1 gnd |
| subject_GND | (DE-588)4371006-2 (DE-588)4045687-0 (DE-588)4282992-6 (DE-588)4024069-1 (DE-588)4143413-4 |
| title | Antisense research and application [with 42 tables] |
| title_auth | Antisense research and application [with 42 tables] |
| title_exact_search | Antisense research and application [with 42 tables] |
| title_full | Antisense research and application [with 42 tables] contributors S. Agrawal ... Ed. Stanley T. Crooke |
| title_fullStr | Antisense research and application [with 42 tables] contributors S. Agrawal ... Ed. Stanley T. Crooke |
| title_full_unstemmed | Antisense research and application [with 42 tables] contributors S. Agrawal ... Ed. Stanley T. Crooke |
| title_short | Antisense research and application |
| title_sort | antisense research and application with 42 tables |
| title_sub | [with 42 tables] |
| topic | Antisense Elements [Genetics] cabt Pharmacology cabt Antisense-ketens gtt Farmacotherapie gtt Genexpressie gtt Antisense Elements (Genetics) pharmacology Antisense Elements (Genetics) therapeutic use Antisense nucleic acids Therapeutic use Antisense-Oligonucleotide (DE-588)4371006-2 gnd Pharmakologie (DE-588)4045687-0 gnd Antisense-Nucleinsäuren (DE-588)4282992-6 gnd Heilmittel (DE-588)4024069-1 gnd |
| topic_facet | Antisense Elements [Genetics] Pharmacology Antisense-ketens Farmacotherapie Genexpressie Antisense Elements (Genetics) pharmacology Antisense Elements (Genetics) therapeutic use Antisense nucleic acids Therapeutic use Antisense-Oligonucleotide Pharmakologie Antisense-Nucleinsäuren Heilmittel Aufsatzsammlung |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=007968111&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| volume_link | (DE-604)BV002390716 |
| work_keys_str_mv | AT crookestanleyt antisenseresearchandapplicationwith42tables AT agrawalsudhir antisenseresearchandapplicationwith42tables |