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Foreword by Dr Hamaguchi xiii Foreword by Dr Noyori xv Preface xvii 1 Control of DNA Packaging by Block Catiomers for Systemic Gene Delivery System 1 Kensuke Osada
1.1 Introduction 1
1.2 Packaging of pDNA by Block Catiomers 2
1.2.1 Rod-Shaped Packaging of pDNA 3
1.2.2 Rod Shape or Globular Shape 5
1.3 PolyplexMicelles as a Systemic Gene Delivery System 6
1.3.1 Stable Encapsulation of pDNAWithin Polyplex Micelles for Systemic Delivery 6
1.3.2 PolyplexMicelles for Efficient Cellular Entry 9
1.3.3 PolyplexMicelles for Safe Endosome Escape 11
1.3.4 PolyplexMicelles for Nuclear Translocation 13
1.3.5 PolyplexMicelles for Efficient Transcription 13
1.4 Design Criteria of Block Catiomers Toward Systemic Gene Therapy 14
1.5 Rod Shape or Toroid Shape 17
1.6 Summary 18 References 18 2 Manipulation of Molecular Architecture with DNA 25 Akinori Kuzuya
2.1 Introduction 25
2.2 Molecular Structure of DNA 25
2.3 Immobile DNA Junctions 26
2.4 Topologically Unique DNA Molecules 28
2.5 DNA Tiles and Their Assemblies 28
2.6 DNA Origami 30
2.7 DNA Origami as a Molecular Peg Board 32
2.8 Molecular Machines Made of DNA Origami 33
2.9 DNA Origami Pinching Devices 33
2.10 Novel Design Principles 35
2.11 DNA-PAINT: An Application of DNA Devices 36
2.12 Prospects 36 References 36 3 Chemical Assembly Lines for Skeletally Diverse Indole Alkaloids 43 Hiroki Oguri
3.1 Introduction 43
3.2 Macmillan''s Collective Total Synthesis by Means of Organocascade Catalysis 45
3.3 Systematic Synthesis of Indole Alkaloids Employing Cyclopentene Intermediates by the Zhu Group 52
3.4 Biogenetically Inspired Synthesis Employing a Multipotent Intermediate by the Oguri Group 58 References 68 4 Molecular Technology for Injured Brain Regeneration 71 Itsuki Ajioka
4.1 Introduction 71
4.2 Biology of Angiogenesis 71
4.3 Angiogenesis for Injured Brain Regeneration 73
4.4 Molecular Technology to Promote Angiogenesis 74
4.5 Biology of Cell Cycle 75
4.6 Biology of Neurogenesis 77
4.7 Molecular Technology to Promote Neuron Regeneration 78
4.8 Conclusion 80 References 80 5 Engineering the Ribosomal Translation Systemto Introduce Non-proteinogenic Amino Acids into Peptides 87 Takayuki Katoh
5.1 Introduction 87
5.2 Decoding the Genetic Code 88
5.3 Aminoacylation of tRNA by Aminoacyl-tRNA Synthetases 90
5.4 Methods for Preparing Noncanonical Aminoacyl-tRNAs 91
5.4.1 Ligation of Aminoacyl-pdCpA Dinucleotide with tRNA Lacking the 3'-Terminal CA 91
5.4.2 Post-aminoacylationModification of Aminoacyl-tRNA 93
5.4.3 Misacylation of Non-proteinogenic Amino Acids by ARSs 94
5.4.4 Flexizyme, an Aminoacylation Ribozyme 94
5.5 Methods for Assigning Non-proteinogenic Amino Acids to the Genetic Code 95
5.5.1 The Nonsense Codon Method 96
5.5.2 Genetic Code Reprogramming 97
5.5.3 The Four-base Codon Method 98
5.5.4 The Nonstandard Base Method 100
5.6 Limitation of the Incorporation of Noncanonical Amino Acids: Substrate Scope 101
5.7 Improvement of the Substrate Tolerance of Ribosomal Translation 103
5.8 Ribosomally Synthesized Noncanonical Peptides as Drug Discovery Platforms 104
5.9 Summary and Outlook 105 References 106 6 Development of Functional Nanoparticles and Their Systems Capable of Accumulating to Tumors 113 Satoru Karasawa
6.1 Introduction 113
6.2 Accumulation Based on Aberrant Morphology and Size 114
6.3 Accumulation Based on Aberrant pH Microenvironment 117
6.4 Accumulation Based on Temperature of Tumor Microenvironment 124
6.5 Perspective 129 References 129 7 Glycan Molecular Technology for Highly Selective In Vivo Recognition 131 Katsunori Tanaka
7.1 Molecular Technology for Chemical Glycan Conjugation 133
7.1.1 Conjugation to Lysine 133
7.1.2 Conjugation to Cysteine 133
7.1.3 Bioorthogonal Conjugation 136
7.1.4 Enzymatic Glycosylation 136
7.2 In Vivo Kinetic Studies of Monosaccharide-Modified Proteins 137
7.2.1 Dissection-Based Kinetic and Biodistribution Studies: Effects of Protein Modification by Galactose, Mannose, and Fucose 137
7.2.2 Noninvasive Imaging of In Vivo Kinetic and Organ-Specific Accumulation of Monosaccharide-Modified Proteins 138
7.3 In Vivo Kinetic Studies of Oligosaccharide-Modified Proteins 139
7.3.1 In Vivo Kinetics of Proteins Modified by a Few Molecules of N -glycans 139
7.3.2 In Vivo Kinetics of Proteins Modified by Many N -glycans: Homogeneous N -glycoalbumins 141
7.3.3 In Vivo Kinetics of Proteins Modified by Many N -glycans: Heterogeneous N -glycoalbumins 145
7.3.4 Tumor Targeting by N -glycoalbumins 148
7.3.5 Glycan Molecular Technology on Live Cells: Tumor Targeting by N -glycan-Engineered Lymphocytes 148
7.4 Glycan Molecular Technology Adapted as Metal Carriers: In Vivo Metal-Catalyzed Reactions within Live Animals 150
7.5 Concluding Remarks 153 Acknowledgments 155 References 155 8 Molecular Technology Toward Expansion of Nucleic Acid Functionality 165 Michiko Kimoto and Kiyohiko Kawai
8.1 Introduction 165
8.2 Molecular Technologies that Enable Genetic Alphabet Expansion 168
8.2.1 Nucleotide Modification 168
8.2.2 Unnatural Base Pairs (UBPs) asThird Base Pairs Toward Expansion of Nucleic Acid Functionality 168
8.2.3 High-Affinity DNA Aptamer Generation Using the Expanded Genetic Alphabet 169
8.3 Molecular Technologies that Enable Fluorescence Blinking Control 171
8.3.1 Single Molecule Detection Based on Blinking Observations 171
8.3.2 Blinking Kinetics 172
8.3.3 Control of Fluorescence Blinking by DNA Structure 174
8.3.3.1 Triplet Blinking 174
8.3.3.2 Redox Blinking 175
8.3.3.3 Isomerization Blinking 176
8.4 Conclusions 178 Acknowledgments 178 References 178 9 Molecular Technology for Membrane Functionalization 183 MichioMurakoshi and TakahiroMuraoka
9.1 Introduction 183
9.2 Synthetic Approach for Membrane Functionalization 185
9.2.1 Formation of Multipass Transmembrane Structure 185
9.2.2 Formation of Supramolecular Ion Channels 187
9.2.3 Demonstration of Ligand-Gated Ion Transportation 187
9.2.4 Light-Triggered Membrane Budding 190
9.3 Semi-biological Approach for Membrane Functionalization 191
9.3.1 Mechanical Analysis of the Transmembrane Structure of Membrane Proteins 191
9.3.2 Development of the Nanobiodevice Using a Membrane Protein Expressing in the Inner Ear 193
9.3.3 Improvement of Protein Performance by Genetic Engineering 198 References 199 10 Molecular Technology for Degradable Synthetic Hydrogels for Biomaterials 203 Hiroharu Ajiro and Takamasa Sakai Scope of the
Chapter 203
10.1 Degradation Behavior of Hydrogels 203
10.2 Polylactide Copolymer 205
10.3 Trimethylene Carbonate Derivatives 207
10.4 Polyurethane 211 References 213 11 Molecular Technology for Epigenetics Toward Drug Discovery 219 Takayoshi Suzuki
11.1 Introduction 219
11.2 Epigenetics 219
11.3 Isozyme-Selective Histone Deacetylase (HDAC) Inhibitors 221
11.3.1 Identification of HDAC3-Selective Inhibitors by Click Chemistry Approach 221
11.3.2 Identification of HDAC8-Selective Inhibitors by Click Chemistry Approach and Structure-Based Drug Design 224
11.3.3 Identification of HDAC6-Insensitive Inhibitors Using C-H Activation Reaction 224
11.3.4 Identification of HDAC6-Selective Inhibitors by Substrate-Based Drug Design 228
11.3.5 Identification of SIRT1-Selective Inhibitors by Target-Guided Synthesis 228
11.3.6 Identification of SIRT2-Selective Inhibitors by Structure-Based Drug Design and Click Chemistry Approach 232
11.4 Histone Lysine Demethylase (KDM) Inhibitors 234
11.4.1 Identification of KDM4C Inhibitors by Structure-Based Drug Design 235
11.4.2 Identification of KDM5A Inhibitors by Structure-Based Drug Design 237
11.4.3 Identification of KDM7B Inhibitors by Structure-Based Drug Design 238
11.4.4 Identification of LSD1 Inhibitors by Target-Guided Synthesis 239
11.4.5 Small-Molecule-Based Drug Delivery System Using LSD1 and its Inhibitor 250
11.5 Summary 253 References 254 12 Molecular Technology for Highly Efficient Gene Silencing: DNA/RNA Heteroduplex Oligonucleotides 257 Kotaro Yoshioka, Kazutaka Nishina, Tetsuya Nagata, and Takanori Yokota
12.1 Introduction 257
12.2 Therapeutic Oligonucleotides 257
12.2.1 siRNA 257
12.2.2 ASO 258
12.3 Chemical Modifications ofTherapeutic Oligonucleotide 259
12.3.1 Modifications of Internucleotide Linkage 259
12.3.2 Modifications of Sugar Moiety 260
12.4 Ligand Conjugation for DDS 261
12.4.1 Development of Ligand Molecules for Therapeutic Oligonucleotides 261
12.4.2 Vitamin E for Ligand Molecule 261
12.4.3 siRNA Conjugated with Tocopherol 261
12.4.4 ASO Conjugated with Tocopherol 261
12.5 DNA/RNA Heteroduplex Oligonucleotide 262
12.5.1 Basic Concept of Heteroduplex Oligonucleotide 26