| Author: |
Andrew B. Hughes
|
| Release at: | 2011 |
| Pages: | 538 |
| Edition: |
Volume 4 - Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis
|
| File Size: | 6 MB |
| File Type: | |
| Language: | English |
Content of Amino Acids, Peptides and Proteins in Organic Chemistry
1 Protection Reactions 1
Vommina V. Sureshbabu and Narasimhamurthy Narendra
1.1 General Considerations 1
1.2 a-Amino Protection (Na Protection) 4
1.2.1 Non-Urethanes 4
1.2.1.1 Acyl Type 4
1.2.1.1.1 Monoacyl Groups 5
1.2.1.1.2 Groups Cleavable via Lactam Formation 6
1.2.1.1.3 Diacyl Groups 7
1.2.1.2 Phosphine-Type Groups 10
1.2.1.3 Sulfonyl-Type Groups 10
1.2.1.4 Alkyl-Type Groups 11
1.2.1.4.1 Triphenylmethyl (Trityl or Trt) Group 11
1.2.1.4.2 Benzhydryl Groups 12
1.2.1.4.3 N,N-Bis-Benzyl Protection 12
1.2.1.4.4 Vinyl Groups 12
1.2.1.5 Sulfanyl-Type Groups 13
1.2.2 Urethanes (Carbamates or Alkyloxycarbonyl Groups) 14
1.2.2.1 Formation of the Urethane Bond 16
1.2.2.2 Urethanes Derived from Primary Alcohols 16
1.2.2.2.1 Benzyloxycarbonyl (Cbz or Z) Group 16
1.2.2.2.2 Urethanes Cleaved by b-Elimination 19
1.2.2.2.3 Urethanes Cleaved via Michael-Type Addition 24
1.2.2.2.4 Allyloxycarbonyl (Aloc) Group 25
1.2.2.3 Urethane Groups Derived from Secondary Alcohols 25
1.2.2.4 Urethanes Derived from Tertiary Alcohols 25
1.2.2.4.1 tert-Butoxycarbonyl (Boc) Group 25
1.2.2.4.2 Boc Analogs 28
1.2.2.5 Other Aspects of Urethane Protectors 29
1.2.2.5.1 Formation of Dipeptide Impurities during the Introduction
of Urethanes and Protocols to Overcome It 29
1.2.2.5.2 Introduction of Urethanes via Transprotection 30
1.2.2.5.3 Protection of the Nitrogen of a-Amino Acid
N-Carboxy Anhydrides (NCAs) 31
1.2.2.5.4 Na, Na-bis-Protected Amino Acids 32
1.2.3 Other Na-Protecting Groups 32
1.2.3.1 a-Azido Acids as a-Amino Acid Precursors 33
1.2.3.2 One-Pot Na Protection and Ca Activation 33
1.2.3.3 Effect of Na-Protecting Groups in the Synthesis of NMAs 33
1.3 Carboxy Protection 34
1.3.1 Methyl and Ethyl Esters 35
1.3.1.1 Substituted Methyl and Ethyl Esters 36
1.3.2 Benzyl Ester 36
1.3.2.1 Cleavage 36
1.3.3 Substituted Benzyl Esters 38
1.3.4 tert-Butyl Ester 38
1.3.5 Other Acid-Labile Esters 39
1.3.6 Temporary a-Carboxy Protection 39
1.3.7 a-Carboxy Protectors as Precursors to Useful Amino
Acid Derivatives: Formation of Acid Hydrazides 41
1.4 Side-Chain Protection 41
1.4.1 o-Amino Group of Diamino Acids 41
1.4.2 Guanidino Group of Arg 43
1.4.2.1 Protection Through Protonation 43
1.4.2.2 Nitration 44
1.4.2.3 Arg Precursors 45
1.4.3 Imidazole Group of His 45
1.4.4 Indole Group of Trp 48
1.4.5 o-Amido Group of Asn and Gln 49
1.4.6 b-Thiol Group of Cys 50
1.4.6.1 Common Side-Reactions with S-Protected Cys Derivatives 51
1.4.6.1.1 Racemization 51
1.4.6.1.2 b-Elimination 51
1.4.6.1.3 Oxidation 51
1.4.6.2 Synthesis of Peptides Using Cystine as ‘‘Self-Protected’’ Cys 51
1.4.7 Thioether Group of Met 53
1.4.8 Hydroxy Group of Ser, Thr, and the Phenolic Group of Tyr 54
1.4.9 o-Carboxy Group of Asp and Glu 55
1.4.9.1 Aspartimide Formation 55
1.5 Photocleavable Protections 57
1.6 Conclusions 58
1.7 Experimental Procedures 59
1.7.1 Protection Reactions 59
1.7.1.1 General Procedure for the Preparation of Tfa-Arg-OH 59
1.7.1.2 General Procedure for the Preparation of Na-Phthaloyl Amino Acids using N (Ethoxycarbonyl)phthalimide 59
1.7.1.3 General Procedure for the Preparation of Na-Trt-Amino Acids 59
1.7.1.4 General Procedure for the Preparation of Na-Ns-Amino Acids 60
1.7.1.5 General Procedure for the Preparation of Na-Z-Amino Acids 61
1.7.1.5.1 Method A: Using Z-Cl 61
1.7.1.5.2 Method B: Using Z-OSu 62
1.7.1.6 General Procedures for the Preparation of Na-Fmoc-Amino Acids 62
1.7.1.6.1 Method A: Using Fmoc-OSu 62
1.7.1.6.2 Method B: Using Fmoc-Cl and N,O-bis-TMS-Amino Acids 62
1.7.1.6.3 Method C: Using Fmoc-Cl in the Presence of Zinc Dust 63
1.7.1.6.4 Method D: Using Fmoc-N3 63
1.7.1.7 General Procedure for the Preparation of Na-Nsc-Amino Acids 64
1.7.1.8 General Procedure for the Preparation of Na-Bsmoc-Amino Acids 64
1.7.1.9 General Procedure for the Preparation of Na-Aloc-Amino Acids 65
1.7.1.10 General Procedures for the Preparation of Na-Boc-Amino Acids 65
1.7.1.10.1 Method A: Using (Boc)2O 65
1.7.1.10.2 Method B: Using Boc-ON 65
1.7.1.10.3 Method C: Using Boc-N3 66
1.7.1.11 General Procedure for the Preparation of N,N0-di-Boc-Amino Acids 66
1.7.1.12 General Procedure for the Preparation of Na -Bpoc-Amino Acids 67
1.7.1.13 General Procedures for the Preparation of Amino Acid Methyl Esters 68
1.7.1.13.1 Preparation of Amino Acid Methyl Ester Hydrochloride Salts 68
1.7.1.13.2 Isolation of Amino Acid Methyl Esters: Deprotonation of the Hydrochloride Salt Using Zinc Dust 69
1.7.1.13.3 Glutamic Acid a-Methyl, c-tert-Butyl Diester Using Diazomethane 69
1.7.1.13.4 Z-Glu-OMe via Methanolysis of Cyclic Anhydride 69
1.7.1.14 General Procedure for the Preparation of Amino Acid Ethyl Esters 69
1.7.1.15 General Procedure for the Preparation of Amino Acid Benzyl Ester p Toluenesulfonate Salts 70
1.7.1.15.1 Preparation of Amino Acid Benzyl Ester p-Toluenesulfonate Salts Under Microwave Irradiation 70
1.7.1.16 General Procedure for the Preparation of tert-Butyl Esters of Na-Unprotected Amino Acids Using Isobutene 71
1.7.1.16.1 Preparation of Z-Phe-OtBu by the Silver Salt Method 71
1.7.1.17 General Procedure for Concomitant Protection and Activation
of Amino Acids Using Pentafluorophenyl Carbonate 80
1.7.2 Deprotection Reactions 81
1.7.2.1 Removal of the Phth Group by Hydrazinolysis 81
1.7.2.2 Removal of the Nps Group 81
1.7.2.3 Removal the Z-group 82
1.7.2.3.1 Protocol A: Employing CH 82
1.7.2.3.2 Protocol B: Employing Silylhydride 82
1.7.2.3.3 Protocol C: Through CTH using 1,4-Cyclohexadieneas
Hydrogen Donor 83
1.7.2.4 Cleavage of the Fmoc Group 83
1.7.2.4.1 Method A: Using TAEA [67] 83
1.7.2.4.2 Method B: Using DEA: Simultaneous Removal of the Fmoc Group
and 9-Fluorenylmethyl Ester 83
1.7.2.5 Cleavage of the Boc Group 84
1.7.2.5.1 Protocol A: Removal of the Boc group with TFA in the Presence of Scavengers 84
1.7.2.5.2 Protocol B: Cleavage of Boc Group with TMS/Phenol 84
1.7.2.6 Transprotection of Na-Protecting Groups: Fmoc-Met-OH to Boc-Met-OH 84
1.7.2.7 Selective Methyl Ester Hydrolysis in the Presence of the Na-Fmoc Group 84
1.7.2.8 Cleavage of tert-Butyl Ester Using BF3Et2O 84
1.7.2.9 Selective Cleavage of Phenacyl Ester in the Presence of the Na-Nosyl Group 85
1.7.2.10 Removal of the Trt Group (Iodolysis) 85
1.7.2.11 Deprotection of the Pbf Group from Z-Arg(Pbf)-OH 85
1.7.2.12 Removal of the Phenoc Group through Photolysis 85
1.7.2.13 Conversion of the DCHA Salt of Na-Protected Amino Acids into Free Acids 85
References 86
Part One Amino Acid-Based Peptidomimetics 99
2 Huisgen Cycloaddition in Peptidomimetic Chemistry 101
Daniel Sejer Pedersen and Andrew David Abell
2.1 Introduction 101
2.2 Huisgen [2 þ 3] Cycloaddition Between Azides and
Acetylenes 102
2.3 Mechanistic Consideration for the Cu-Huisgen
and Ru-Huisgen Cycloadditions 103
2.4 Building Blocks for the Synthesis of Triazole-Modified
Peptidomimetics 106
2.5 Cyclic Triazole Peptidomimetics 109
2.6 Acyclic Triazole Peptidomimetics 113
2.7 Useful Experimental Procedures 121
2.7.1 Monitoring Huisgen Cycloadditions and Characterizing
Triazoles 121
2.7.2 General Procedure for the Synthesis of 1,4-Triazoles
Using Cu-Huisgen Cycloaddition 122
2.7.3 General Procedure for the Synthesis of 1,5-Triazoles
Using Ru-Huisgen Cycloaddition 123
References 124
3 Recent Advances in b-Strand Mimetics 129
Wendy A. Loughlin and David P. Fairlie
3.1 Introduction 129
3.1.1 b-Strands 129
3.1.2 b-Sheets 130
3.1.3 Differences in Strand/Sheet/Turn/Helix Recognition 130
3.1.4 Towards b-Strand Mimetics 131
3.2 Macrocyclic Peptidomimetics 133
3.3 Acyclic Compounds 135
3.4 Aliphatic and Aromatic Carbocycles 136
3.5 Ligands Containing One Ring with One Heteroatom (N) 137
3.6 Ligands Containing One or Multiple Rings with
One Heteroatom (O, S) 138
3.7 Ligands Containing One Ring with Two Heteroatoms (N,N) 139
3.8 Ligands Containing One Ring with Two Heteroatoms (N,S)
or Three Heteroatoms (N,N,S or N,N,N) 140
3.9 Ligands Containing Two Rings with One Heteroatom (N or O) 140
3.10 Ligands Containing Two Rings with Two or Three
Heteroatoms (N,N or N,S or N,N,N) 141
3.11 Conclusions 142
References 143
Part Two Medicinal Chemistry of Amino Acids 149
4 Medicinal Chemistry of a-Amino Acids 151
Lennart Bunch and Povl Krogsgaard-Larsen
4.1 Introduction 151
4.2 Glutamic Acid 151
4.3 Conformational Restriction 153
4.3.1 Synthesis – General Considerations 154
4.3.2 Case Study: Synthesis of DCAN 155
4.3.3 Case Study: Synthesis of LY354740 157
4.3.4 Case Study: Synthesis of ABHD-V and ABHD-VI 158
4.4 Bioisosterism 159
4.4.1 Case Study: Design and Synthesis of AMPA 160
4.4.2 Case Study: Design and Synthesis of Thioibotenic Acid 161
4.5 Structure–Activity Studies 162
4.5.1 Case Study: AMPA Analogs 162
4.5.2 Case Study: 4-Substituted Glu analogs 163
4.6 Conclusions 168
References 169
5 Medicinal Chemistry of Alicyclic b-Amino Acids 175
Nils Griebenow
5.1 Introduction 175
5.2 Five-Membered Alicyclic b-Amino Acids 175
5.3 Six-Membered Alicyclic b-Amino Acids 183
References 186
6 Medicinal Chemistry of a-Hydroxy-b-Amino Acids 189
Zyta Ziora, Mariusz Skwarczynski, and Yoshiaki Kiso
6.1 Introduction 189
6.2 a-Hydroxy-b-Amino Acids 189
6.2.1 a-Hydroxy-b-Amino Acids Occurring in Natural Products 189
6.2.2 Synthesis of a-Hydroxy-b-Amino Acids 191
6.2.2.1 Isoserine 191
6.2.2.2 Isothreonine 193
6.2.2.3 Phenylisoserine 197
6.2.2.4 Norstatines 197
6.2.2.5 3-Amino-2-Hydroxydecanoic Acid and its Analogs 204
6.2.2.6 Synthetic Demands 205
6.3 Antibacterial Agents 205
6.4 Inhibitors of Aminopeptidases 207
6.5 Aspartyl Proteases Inhibitors 211
6.5.1 Renin Inhibitors 212
6.5.2 HIV-1 Protease Inhibitors 216
6.5.3 HTLV-I Inhibitors 220
6.5.4 Plasmepsin II Inhibitors 222
6.5.5 BACE-1 Inhibitors 224
6.6 Paclitaxel and its Derivatives 228
References 234
7 Peptide Drugs 247
Chiara Falciani, Alessandro Pini, and Luisa Bracci
7.1 Lights and Shades of Peptide and Protein Drugs 247
7.2 Peptide Drugs Available on the Market 249
7.2.1 Natriuretic Peptide (Nesiritide) 249
7.2.2 Oxytocin 249
7.2.3 Vasopressin 250
7.2.4 Desmopressin 251
7.2.5 Blood Coagulation Inhibitors 251
7.2.5.1 Bivalirudin 251
7.2.5.2 Integrilin (Eptifibatide) 251
7.2.6 Gonadotropin-Releasing Hormone Agonists and
Antagonists 251
7.2.6.1 Gonadorelin 251
7.2.6.2 Lupron(Leuprolide) 252
7.2.6.3 Cetrorelix 253
7.2.6.4 Degarelix 253
7.2.7 Antihyperglycemics 254
7.2.7.1 Symlin (Pramlintide) 254
7.2.7.2 Exendin-4 254
7.2.7.3 Liraglutide 255
7.2.8 Icatibant 255
7.2.9 Sermorelin 256
7.2.10 Calcitonin 256
7.2.11 Parathyroid Hormone 256
7.2.12 Cyclosporine 257
7.2.13 Fuzeon 257
7.3 Approved Peptides in Oncology 258
7.3.1 Bortezomib 259
7.3.2 Actinomycin D 259
7.3.3 Marimastat 260
7.3.4 Octreotide 260
7.3.5 Vapreotide 261
7.3.6 Octreoscan 262
7.4 Antimicrobial peptides 263
7.4.1 Polymyxin 265
7.4.2 Daptomycin 266
7.4.3 Gramicidin S 267
7.5 Perspectives 267
7.5.1 Branched Peptides as Tumor-Targeting Agents 268
7.5.2 Branched Peptides as Antimicrobials 270
References 271
8 Oral Bioavailability of Peptide and Peptidomimetic Drugs 277
Arik Dahan, Yasuhiro Tsume, Jing Sun, Jonathan M. Miller,
and Gordon L. Amidon
8.1 Introduction 277
8.2 Fundamental Considerations of Intestinal Absorption 277
8.3 Barriers Limiting Oral Peptide/Peptidomimetic
Drug Bioavailability 279
8.4 Strategies to Improve Oral Bioavailability of Peptide-Based Drugs 280
8.4.1 Chemical Modifications 280
8.4.1.1 Prodrug Approach 280
8.4.1.2 Structural Modifications 281
8.4.2 Formulation Technologies 284
8.4.2.1 Absorption Enhancers 284
8.4.2.2 Coadministration with Protease Inhibitors 285
8.4.2.3 Formulation Vehicles 285
8.4.2.4 Site-Specific Delivery 286
8.5 Conclusions 287
References 287
9 Asymmetric Synthesis of b-Lactams via the Staudinger Reaction 293
Monika I. Konaklieva and Balbina J. Plotkin
9.1 Introduction 293
9.2 Staudinger Reaction 293
9.3 Influence of the Geometry of the Imine on Stereoselectivity
in the Reaction 294
9.4 Influence of the Polarity of the Solvent on Stereoselectivity
of the Reaction 296
9.5 Influence of the Isomerization of the Imine Prior
to its Nucleophilic Attack onto the Ketene Stereoselectivity
in the Reaction 296
9.6 Influence of the Order of Addition of the Reactants
to the Reaction 297
9.7 Influence of Chiral Substituents on the Stereoselectivity
of the Reaction 298
9.8 Asymmetric Induction from the Imine Component 298
9.9 Asymmetric Induction from the Ketene Component 305
9.10 Double Asymmetric Cycloinduction 308
9.11 Influence of Catalysts on the Stereoselectivity
of the Reaction 309
9.11.1 General Procedure for b-Lactams 106 with Proton Sponge 312
9.11.2 General Procedure for the Tandem Nucleophile/Lewis
Acid-Promoted Synthesis of b-Lactams 110 312
9.11.3 General Procedure for Catalytic Asymmetric
Synthesis of Trans-b-Lactams 113 314
9.11.4 Example for Kinugasa Reaction with Cu (II) Catalyst 316
9.11.4.1 General Procedure for Catalytic Asymmetric Synthesis
of b-Lactams 122 316
9.12 Conclusions 316
References 317
10 Advances in N- and O-Glycopeptide Synthesis – A Tool to
Study Glycosylation and Develop New Therapeutics 321
Ulrika Westerlind and Horst Kunz
10.1 Introduction 321
10.2 Synthesis of O-Glycopeptides 324
10.2.1 Synthesis of Mucin-Type Glycopeptides 325
10.2.1.1 Synthesis of Tumor-Associated Glycopeptides and
Glycopeptide Vaccines 325
10.2.1.1.1 Synthesis of Tn, T, Sialyl-Tn, and Sialyl-T Glycosylated Amino
Acid Building Blocks 325
10.2.1.1.2 Synthesis of Tn, T, Sialyl-Tn, and Sialyl-T Glycopeptides and
Vaccines 329
10.2.1.2 Synthesis of Glycopeptide Recognition Domain of P-Selectin
Glycoprotein Ligand-1 331
10.2.1.2.1 Synthesis of a Core 2 sLex Amino Acid Building Block Including
a sLex Mimic 332
10.2.1.2.2 Synthesis of Unsulfated and Sulfated Core 2 sLex and Core 2 sLex
Mimic PSGL-1 Glycopeptides 334
10.2.1.2.3 Chemoenzymatic Synthesis of Unsulfated and Sulfated sLex
PSGL-1 Glycopeptide 336
10.2.2 Synthesis of Other Types of O-Glycopeptides 339
10.2.2.1 Synthesis of Fmoc-GlcNAc-Ser/Thr Amino Acids 340
10.2.2.2 Synthesis of Estrogen Receptor Peptides for Conformational
Analysis 340
10.3 Synthesis of N-Glycopeptides 342
10.3.1 Synthesis of RNase C Glycoprotein 343
10.3.2 Synthesis of Erythropoietin N-Glycopeptide Fragment 1–28 346
10.3.2.1 Synthesis of Biantennary Dodecasaccharide 346
10.3.2.2 Synthesis of N-Glycopeptide Fragment 1–28 348
10.3.3 Chemoenzymatic Synthesis of a HIV GP120 V3 Domain
N-Glycopeptide 350
10.3.3.1 Synthesis of the Oxazoline Tetrasaccharide Donor 350
10.3.3.2 Synthesis of Fmoc-GlcNAc-Asn Amino Acid Building Block 351
10.3.3.3 Synthesis of V3 Cyclic GlcNAc Peptide and Endo A Coupling
with Man3GlcNAc Oxazoline Donor 352
References 353
11 Recent Developments in Neoglycopeptide Synthesis 359
Margaret A. Brimble, Nicole Miller, and Geoffrey M. Williams
11.1 Introduction 359
11.2 Neoglycoside and Neoglycopeptide Synthesis 361
11.2.1 S-Glycosides 361
11.2.2 N-Glycosides 362
11.2.3 O-Glycosides 364
11.2.4 C-Glycosides 365
11.2.5 C1⁄4N Linkage 365
11.3 Protein Side-Chain Modifications 366
11.3.1 Modifications of Cysteine Side-Chains 366
11.3.2 Modifications of Lysine Side-Chains 369
11.3.3 Other Side-Chain Modifications 370
11.4 Cu(I)-Catalyzed Azide–Alkyne ‘‘Click’’ Cycloaddition 372
11.4.1 General Aspects of Cu(I)-Catalyzed Azide–Alkyne cycloaddition 372
11.4.2 Neoglycoside and Neoglycopeptide Synthesis via CuAAC 373
11.4.3 CuAAC and Neoglycoproteins 376
11.5 Cross-Metathesis 378
11.6 Application of Neoglycopeptides as
Synthetic Vaccines 380
11.7 Enzymatic, Molecular, and Cell Biological
Techniques 384
11.7.1.1 Enzymatic Glycoprotein Synthesis 385
11.7.2 Molecular and Cell Biological Techniques 385
References 386
Part Three Amino Acids in Combinatorial Synthesis 393
12 Combinatorial/Library Peptide Synthesis 395
Michal Lebl
12.1 Introduction 395
12.2 High-Throughput Synthesis of Peptides 396
12.2.1 Parallel Peptide Synthesis 396
12.2.2 Directed Sorting 400
12.3 Synthesis of Peptide Arrays 402
12.4 Peptide Libraries 406
12.4.1 Synthesis of Peptide Mixtures 406
12.4.2 Synthesis of Peptides on a Mixture of Particles 409
12.4.2.1 Determination of the Structure of a Peptide on an
Individual Bead 416
12.4.3 Solution-Based Screening of OBOC Libraries 418
12.5 Future of Peptide Libraries 421
12.6 Synthetic Protocols 421
12.6.1 Pin Synthesis 421
12.6.2 SPOT Synthesis 422
12.6.3 Synthesis in Tea-Bags 422
12.6.4 Synthesis on Cotton 423
12.6.4.1 Modification of the Cotton Carrier 423
12.6.5 Split-and-Mix Synthesis of OBOC
Noncleavable Libraries 424
12.6.6 Preparation of Dual-Layer Beads 425
12.6.7 Preparation of Library of Libraries 426
12.6.8 Preparation of OBOC Libraries for Testing in
Solution 426
12.6.8.1 Synthesis of Multicleavable Linker 426
12.6.8.2 Synthesis of the Library 428
12.6.8.3 Quality Control of the Doubly Releasable Library 428
12.6.8.4 Two-Stage Release Assay in 96-Well Microassay Plates 429
12.6.9 Synthesis of the Positional Scanning Library 430
12.6.10 Synthesis of the Dual Defined Iterative
Hexapeptide Library 430
12.6.11 Acylation Monitoring by Bromophenol Blue 431
References 432
13 Phage-Displayed Combinatorial Peptides 451
Renhua Huang, Kritika Pershad, Malgorzata Kokoszka,
and Brian K. Kay
13.1 Introduction 451
13.1.1 Types of Phage Vectors 452
13.1.2 Generation of Combinatorial Peptide Libraries 455
13.1.3 Identifying Peptide Ligands to Protein Targets 458
13.1.4 Mapping Protein–Protein Interactions 461
13.1.5 Identifying Peptide Ligands Binding to Cell Surfaces 463
13.1.6 Mapping Protease Specificity 464
13.1.7 Identifying Peptide Ligands to the Surfaces of Inert Materials 464
13.2 Conclusions 465
References 466
14 Designing New Proteins 473
Michael I. Sadowski and James T. MacDonald
14.1 Introduction 473
14.1.1 Why Design New Proteins? 473
14.1.2 How New is ‘‘New?’’ 474
14.2 Protein Design Methods 475
14.2.1 Computational Design 476
14.2.1.1 Computational Enzyme Design 477
14.2.1.2 Results of Computational Design Experiments 478
14.2.2 Directed Evolution Methods 480
14.2.2.1 Randomization Strategies 480
14.2.2.2 Expression Systems and Assays 481
14.2.3 Design of Protein Interfaces 482
14.3 Protocol for Protein Design 484
14.4 Conclusions 486
References 487
15 Amino Acid-Based Dendrimers 491
Zhengshuang Shi, Chunhui Zhou, Zhigang Liu, Filbert Totsingan,
and Neville R. Kallenbach
15.1 Introduction 491
15.2 Peptide Dendrimer Synthesis: Divergent and
Convergent Approaches 491
15.2.1 Synthesis of the First Peptide Dendrimers: Polylysine
Dendrimers 493
15.2.2 Glutamic/Aspartic Acid, Proline, and Arginine Dendrimers 494
15.2.3 Synthesis of MAPs 497
15.2.4 Synthesis of Peptide Dendrimers Grafted on PAMAM and
other Peptide Dendrimers 500
15.3 Applications of Peptide Dendrimers 502
15.3.1 Initial Efforts on MAPs 502
15.3.2 Peptide Dendrimers as Antimicrobial Agents 502
15.3.3 Peptide Dendrimers as Protein/Enzyme Mimics 504
15.3.4 Peptide Dendrimers as Ion Sensors and MRI Contrast Agents 505
15.3.5 Peptide Dendrimers as DNA/RNA Delivery Vectors 507
15.3.6 Other Application of Peptide Dendrimers 512
15.4 Conclusions 513
References 514
Index 519
Vommina V. Sureshbabu and Narasimhamurthy Narendra
1.1 General Considerations 1
1.2 a-Amino Protection (Na Protection) 4
1.2.1 Non-Urethanes 4
1.2.1.1 Acyl Type 4
1.2.1.1.1 Monoacyl Groups 5
1.2.1.1.2 Groups Cleavable via Lactam Formation 6
1.2.1.1.3 Diacyl Groups 7
1.2.1.2 Phosphine-Type Groups 10
1.2.1.3 Sulfonyl-Type Groups 10
1.2.1.4 Alkyl-Type Groups 11
1.2.1.4.1 Triphenylmethyl (Trityl or Trt) Group 11
1.2.1.4.2 Benzhydryl Groups 12
1.2.1.4.3 N,N-Bis-Benzyl Protection 12
1.2.1.4.4 Vinyl Groups 12
1.2.1.5 Sulfanyl-Type Groups 13
1.2.2 Urethanes (Carbamates or Alkyloxycarbonyl Groups) 14
1.2.2.1 Formation of the Urethane Bond 16
1.2.2.2 Urethanes Derived from Primary Alcohols 16
1.2.2.2.1 Benzyloxycarbonyl (Cbz or Z) Group 16
1.2.2.2.2 Urethanes Cleaved by b-Elimination 19
1.2.2.2.3 Urethanes Cleaved via Michael-Type Addition 24
1.2.2.2.4 Allyloxycarbonyl (Aloc) Group 25
1.2.2.3 Urethane Groups Derived from Secondary Alcohols 25
1.2.2.4 Urethanes Derived from Tertiary Alcohols 25
1.2.2.4.1 tert-Butoxycarbonyl (Boc) Group 25
1.2.2.4.2 Boc Analogs 28
1.2.2.5 Other Aspects of Urethane Protectors 29
1.2.2.5.1 Formation of Dipeptide Impurities during the Introduction
of Urethanes and Protocols to Overcome It 29
1.2.2.5.2 Introduction of Urethanes via Transprotection 30
1.2.2.5.3 Protection of the Nitrogen of a-Amino Acid
N-Carboxy Anhydrides (NCAs) 31
1.2.2.5.4 Na, Na-bis-Protected Amino Acids 32
1.2.3 Other Na-Protecting Groups 32
1.2.3.1 a-Azido Acids as a-Amino Acid Precursors 33
1.2.3.2 One-Pot Na Protection and Ca Activation 33
1.2.3.3 Effect of Na-Protecting Groups in the Synthesis of NMAs 33
1.3 Carboxy Protection 34
1.3.1 Methyl and Ethyl Esters 35
1.3.1.1 Substituted Methyl and Ethyl Esters 36
1.3.2 Benzyl Ester 36
1.3.2.1 Cleavage 36
1.3.3 Substituted Benzyl Esters 38
1.3.4 tert-Butyl Ester 38
1.3.5 Other Acid-Labile Esters 39
1.3.6 Temporary a-Carboxy Protection 39
1.3.7 a-Carboxy Protectors as Precursors to Useful Amino
Acid Derivatives: Formation of Acid Hydrazides 41
1.4 Side-Chain Protection 41
1.4.1 o-Amino Group of Diamino Acids 41
1.4.2 Guanidino Group of Arg 43
1.4.2.1 Protection Through Protonation 43
1.4.2.2 Nitration 44
1.4.2.3 Arg Precursors 45
1.4.3 Imidazole Group of His 45
1.4.4 Indole Group of Trp 48
1.4.5 o-Amido Group of Asn and Gln 49
1.4.6 b-Thiol Group of Cys 50
1.4.6.1 Common Side-Reactions with S-Protected Cys Derivatives 51
1.4.6.1.1 Racemization 51
1.4.6.1.2 b-Elimination 51
1.4.6.1.3 Oxidation 51
1.4.6.2 Synthesis of Peptides Using Cystine as ‘‘Self-Protected’’ Cys 51
1.4.7 Thioether Group of Met 53
1.4.8 Hydroxy Group of Ser, Thr, and the Phenolic Group of Tyr 54
1.4.9 o-Carboxy Group of Asp and Glu 55
1.4.9.1 Aspartimide Formation 55
1.5 Photocleavable Protections 57
1.6 Conclusions 58
1.7 Experimental Procedures 59
1.7.1 Protection Reactions 59
1.7.1.1 General Procedure for the Preparation of Tfa-Arg-OH 59
1.7.1.2 General Procedure for the Preparation of Na-Phthaloyl Amino Acids using N (Ethoxycarbonyl)phthalimide 59
1.7.1.3 General Procedure for the Preparation of Na-Trt-Amino Acids 59
1.7.1.4 General Procedure for the Preparation of Na-Ns-Amino Acids 60
1.7.1.5 General Procedure for the Preparation of Na-Z-Amino Acids 61
1.7.1.5.1 Method A: Using Z-Cl 61
1.7.1.5.2 Method B: Using Z-OSu 62
1.7.1.6 General Procedures for the Preparation of Na-Fmoc-Amino Acids 62
1.7.1.6.1 Method A: Using Fmoc-OSu 62
1.7.1.6.2 Method B: Using Fmoc-Cl and N,O-bis-TMS-Amino Acids 62
1.7.1.6.3 Method C: Using Fmoc-Cl in the Presence of Zinc Dust 63
1.7.1.6.4 Method D: Using Fmoc-N3 63
1.7.1.7 General Procedure for the Preparation of Na-Nsc-Amino Acids 64
1.7.1.8 General Procedure for the Preparation of Na-Bsmoc-Amino Acids 64
1.7.1.9 General Procedure for the Preparation of Na-Aloc-Amino Acids 65
1.7.1.10 General Procedures for the Preparation of Na-Boc-Amino Acids 65
1.7.1.10.1 Method A: Using (Boc)2O 65
1.7.1.10.2 Method B: Using Boc-ON 65
1.7.1.10.3 Method C: Using Boc-N3 66
1.7.1.11 General Procedure for the Preparation of N,N0-di-Boc-Amino Acids 66
1.7.1.12 General Procedure for the Preparation of Na -Bpoc-Amino Acids 67
1.7.1.13 General Procedures for the Preparation of Amino Acid Methyl Esters 68
1.7.1.13.1 Preparation of Amino Acid Methyl Ester Hydrochloride Salts 68
1.7.1.13.2 Isolation of Amino Acid Methyl Esters: Deprotonation of the Hydrochloride Salt Using Zinc Dust 69
1.7.1.13.3 Glutamic Acid a-Methyl, c-tert-Butyl Diester Using Diazomethane 69
1.7.1.13.4 Z-Glu-OMe via Methanolysis of Cyclic Anhydride 69
1.7.1.14 General Procedure for the Preparation of Amino Acid Ethyl Esters 69
1.7.1.15 General Procedure for the Preparation of Amino Acid Benzyl Ester p Toluenesulfonate Salts 70
1.7.1.15.1 Preparation of Amino Acid Benzyl Ester p-Toluenesulfonate Salts Under Microwave Irradiation 70
1.7.1.16 General Procedure for the Preparation of tert-Butyl Esters of Na-Unprotected Amino Acids Using Isobutene 71
1.7.1.16.1 Preparation of Z-Phe-OtBu by the Silver Salt Method 71
1.7.1.17 General Procedure for Concomitant Protection and Activation
of Amino Acids Using Pentafluorophenyl Carbonate 80
1.7.2 Deprotection Reactions 81
1.7.2.1 Removal of the Phth Group by Hydrazinolysis 81
1.7.2.2 Removal of the Nps Group 81
1.7.2.3 Removal the Z-group 82
1.7.2.3.1 Protocol A: Employing CH 82
1.7.2.3.2 Protocol B: Employing Silylhydride 82
1.7.2.3.3 Protocol C: Through CTH using 1,4-Cyclohexadieneas
Hydrogen Donor 83
1.7.2.4 Cleavage of the Fmoc Group 83
1.7.2.4.1 Method A: Using TAEA [67] 83
1.7.2.4.2 Method B: Using DEA: Simultaneous Removal of the Fmoc Group
and 9-Fluorenylmethyl Ester 83
1.7.2.5 Cleavage of the Boc Group 84
1.7.2.5.1 Protocol A: Removal of the Boc group with TFA in the Presence of Scavengers 84
1.7.2.5.2 Protocol B: Cleavage of Boc Group with TMS/Phenol 84
1.7.2.6 Transprotection of Na-Protecting Groups: Fmoc-Met-OH to Boc-Met-OH 84
1.7.2.7 Selective Methyl Ester Hydrolysis in the Presence of the Na-Fmoc Group 84
1.7.2.8 Cleavage of tert-Butyl Ester Using BF3Et2O 84
1.7.2.9 Selective Cleavage of Phenacyl Ester in the Presence of the Na-Nosyl Group 85
1.7.2.10 Removal of the Trt Group (Iodolysis) 85
1.7.2.11 Deprotection of the Pbf Group from Z-Arg(Pbf)-OH 85
1.7.2.12 Removal of the Phenoc Group through Photolysis 85
1.7.2.13 Conversion of the DCHA Salt of Na-Protected Amino Acids into Free Acids 85
References 86
Part One Amino Acid-Based Peptidomimetics 99
2 Huisgen Cycloaddition in Peptidomimetic Chemistry 101
Daniel Sejer Pedersen and Andrew David Abell
2.1 Introduction 101
2.2 Huisgen [2 þ 3] Cycloaddition Between Azides and
Acetylenes 102
2.3 Mechanistic Consideration for the Cu-Huisgen
and Ru-Huisgen Cycloadditions 103
2.4 Building Blocks for the Synthesis of Triazole-Modified
Peptidomimetics 106
2.5 Cyclic Triazole Peptidomimetics 109
2.6 Acyclic Triazole Peptidomimetics 113
2.7 Useful Experimental Procedures 121
2.7.1 Monitoring Huisgen Cycloadditions and Characterizing
Triazoles 121
2.7.2 General Procedure for the Synthesis of 1,4-Triazoles
Using Cu-Huisgen Cycloaddition 122
2.7.3 General Procedure for the Synthesis of 1,5-Triazoles
Using Ru-Huisgen Cycloaddition 123
References 124
3 Recent Advances in b-Strand Mimetics 129
Wendy A. Loughlin and David P. Fairlie
3.1 Introduction 129
3.1.1 b-Strands 129
3.1.2 b-Sheets 130
3.1.3 Differences in Strand/Sheet/Turn/Helix Recognition 130
3.1.4 Towards b-Strand Mimetics 131
3.2 Macrocyclic Peptidomimetics 133
3.3 Acyclic Compounds 135
3.4 Aliphatic and Aromatic Carbocycles 136
3.5 Ligands Containing One Ring with One Heteroatom (N) 137
3.6 Ligands Containing One or Multiple Rings with
One Heteroatom (O, S) 138
3.7 Ligands Containing One Ring with Two Heteroatoms (N,N) 139
3.8 Ligands Containing One Ring with Two Heteroatoms (N,S)
or Three Heteroatoms (N,N,S or N,N,N) 140
3.9 Ligands Containing Two Rings with One Heteroatom (N or O) 140
3.10 Ligands Containing Two Rings with Two or Three
Heteroatoms (N,N or N,S or N,N,N) 141
3.11 Conclusions 142
References 143
Part Two Medicinal Chemistry of Amino Acids 149
4 Medicinal Chemistry of a-Amino Acids 151
Lennart Bunch and Povl Krogsgaard-Larsen
4.1 Introduction 151
4.2 Glutamic Acid 151
4.3 Conformational Restriction 153
4.3.1 Synthesis – General Considerations 154
4.3.2 Case Study: Synthesis of DCAN 155
4.3.3 Case Study: Synthesis of LY354740 157
4.3.4 Case Study: Synthesis of ABHD-V and ABHD-VI 158
4.4 Bioisosterism 159
4.4.1 Case Study: Design and Synthesis of AMPA 160
4.4.2 Case Study: Design and Synthesis of Thioibotenic Acid 161
4.5 Structure–Activity Studies 162
4.5.1 Case Study: AMPA Analogs 162
4.5.2 Case Study: 4-Substituted Glu analogs 163
4.6 Conclusions 168
References 169
5 Medicinal Chemistry of Alicyclic b-Amino Acids 175
Nils Griebenow
5.1 Introduction 175
5.2 Five-Membered Alicyclic b-Amino Acids 175
5.3 Six-Membered Alicyclic b-Amino Acids 183
References 186
6 Medicinal Chemistry of a-Hydroxy-b-Amino Acids 189
Zyta Ziora, Mariusz Skwarczynski, and Yoshiaki Kiso
6.1 Introduction 189
6.2 a-Hydroxy-b-Amino Acids 189
6.2.1 a-Hydroxy-b-Amino Acids Occurring in Natural Products 189
6.2.2 Synthesis of a-Hydroxy-b-Amino Acids 191
6.2.2.1 Isoserine 191
6.2.2.2 Isothreonine 193
6.2.2.3 Phenylisoserine 197
6.2.2.4 Norstatines 197
6.2.2.5 3-Amino-2-Hydroxydecanoic Acid and its Analogs 204
6.2.2.6 Synthetic Demands 205
6.3 Antibacterial Agents 205
6.4 Inhibitors of Aminopeptidases 207
6.5 Aspartyl Proteases Inhibitors 211
6.5.1 Renin Inhibitors 212
6.5.2 HIV-1 Protease Inhibitors 216
6.5.3 HTLV-I Inhibitors 220
6.5.4 Plasmepsin II Inhibitors 222
6.5.5 BACE-1 Inhibitors 224
6.6 Paclitaxel and its Derivatives 228
References 234
7 Peptide Drugs 247
Chiara Falciani, Alessandro Pini, and Luisa Bracci
7.1 Lights and Shades of Peptide and Protein Drugs 247
7.2 Peptide Drugs Available on the Market 249
7.2.1 Natriuretic Peptide (Nesiritide) 249
7.2.2 Oxytocin 249
7.2.3 Vasopressin 250
7.2.4 Desmopressin 251
7.2.5 Blood Coagulation Inhibitors 251
7.2.5.1 Bivalirudin 251
7.2.5.2 Integrilin (Eptifibatide) 251
7.2.6 Gonadotropin-Releasing Hormone Agonists and
Antagonists 251
7.2.6.1 Gonadorelin 251
7.2.6.2 Lupron(Leuprolide) 252
7.2.6.3 Cetrorelix 253
7.2.6.4 Degarelix 253
7.2.7 Antihyperglycemics 254
7.2.7.1 Symlin (Pramlintide) 254
7.2.7.2 Exendin-4 254
7.2.7.3 Liraglutide 255
7.2.8 Icatibant 255
7.2.9 Sermorelin 256
7.2.10 Calcitonin 256
7.2.11 Parathyroid Hormone 256
7.2.12 Cyclosporine 257
7.2.13 Fuzeon 257
7.3 Approved Peptides in Oncology 258
7.3.1 Bortezomib 259
7.3.2 Actinomycin D 259
7.3.3 Marimastat 260
7.3.4 Octreotide 260
7.3.5 Vapreotide 261
7.3.6 Octreoscan 262
7.4 Antimicrobial peptides 263
7.4.1 Polymyxin 265
7.4.2 Daptomycin 266
7.4.3 Gramicidin S 267
7.5 Perspectives 267
7.5.1 Branched Peptides as Tumor-Targeting Agents 268
7.5.2 Branched Peptides as Antimicrobials 270
References 271
8 Oral Bioavailability of Peptide and Peptidomimetic Drugs 277
Arik Dahan, Yasuhiro Tsume, Jing Sun, Jonathan M. Miller,
and Gordon L. Amidon
8.1 Introduction 277
8.2 Fundamental Considerations of Intestinal Absorption 277
8.3 Barriers Limiting Oral Peptide/Peptidomimetic
Drug Bioavailability 279
8.4 Strategies to Improve Oral Bioavailability of Peptide-Based Drugs 280
8.4.1 Chemical Modifications 280
8.4.1.1 Prodrug Approach 280
8.4.1.2 Structural Modifications 281
8.4.2 Formulation Technologies 284
8.4.2.1 Absorption Enhancers 284
8.4.2.2 Coadministration with Protease Inhibitors 285
8.4.2.3 Formulation Vehicles 285
8.4.2.4 Site-Specific Delivery 286
8.5 Conclusions 287
References 287
9 Asymmetric Synthesis of b-Lactams via the Staudinger Reaction 293
Monika I. Konaklieva and Balbina J. Plotkin
9.1 Introduction 293
9.2 Staudinger Reaction 293
9.3 Influence of the Geometry of the Imine on Stereoselectivity
in the Reaction 294
9.4 Influence of the Polarity of the Solvent on Stereoselectivity
of the Reaction 296
9.5 Influence of the Isomerization of the Imine Prior
to its Nucleophilic Attack onto the Ketene Stereoselectivity
in the Reaction 296
9.6 Influence of the Order of Addition of the Reactants
to the Reaction 297
9.7 Influence of Chiral Substituents on the Stereoselectivity
of the Reaction 298
9.8 Asymmetric Induction from the Imine Component 298
9.9 Asymmetric Induction from the Ketene Component 305
9.10 Double Asymmetric Cycloinduction 308
9.11 Influence of Catalysts on the Stereoselectivity
of the Reaction 309
9.11.1 General Procedure for b-Lactams 106 with Proton Sponge 312
9.11.2 General Procedure for the Tandem Nucleophile/Lewis
Acid-Promoted Synthesis of b-Lactams 110 312
9.11.3 General Procedure for Catalytic Asymmetric
Synthesis of Trans-b-Lactams 113 314
9.11.4 Example for Kinugasa Reaction with Cu (II) Catalyst 316
9.11.4.1 General Procedure for Catalytic Asymmetric Synthesis
of b-Lactams 122 316
9.12 Conclusions 316
References 317
10 Advances in N- and O-Glycopeptide Synthesis – A Tool to
Study Glycosylation and Develop New Therapeutics 321
Ulrika Westerlind and Horst Kunz
10.1 Introduction 321
10.2 Synthesis of O-Glycopeptides 324
10.2.1 Synthesis of Mucin-Type Glycopeptides 325
10.2.1.1 Synthesis of Tumor-Associated Glycopeptides and
Glycopeptide Vaccines 325
10.2.1.1.1 Synthesis of Tn, T, Sialyl-Tn, and Sialyl-T Glycosylated Amino
Acid Building Blocks 325
10.2.1.1.2 Synthesis of Tn, T, Sialyl-Tn, and Sialyl-T Glycopeptides and
Vaccines 329
10.2.1.2 Synthesis of Glycopeptide Recognition Domain of P-Selectin
Glycoprotein Ligand-1 331
10.2.1.2.1 Synthesis of a Core 2 sLex Amino Acid Building Block Including
a sLex Mimic 332
10.2.1.2.2 Synthesis of Unsulfated and Sulfated Core 2 sLex and Core 2 sLex
Mimic PSGL-1 Glycopeptides 334
10.2.1.2.3 Chemoenzymatic Synthesis of Unsulfated and Sulfated sLex
PSGL-1 Glycopeptide 336
10.2.2 Synthesis of Other Types of O-Glycopeptides 339
10.2.2.1 Synthesis of Fmoc-GlcNAc-Ser/Thr Amino Acids 340
10.2.2.2 Synthesis of Estrogen Receptor Peptides for Conformational
Analysis 340
10.3 Synthesis of N-Glycopeptides 342
10.3.1 Synthesis of RNase C Glycoprotein 343
10.3.2 Synthesis of Erythropoietin N-Glycopeptide Fragment 1–28 346
10.3.2.1 Synthesis of Biantennary Dodecasaccharide 346
10.3.2.2 Synthesis of N-Glycopeptide Fragment 1–28 348
10.3.3 Chemoenzymatic Synthesis of a HIV GP120 V3 Domain
N-Glycopeptide 350
10.3.3.1 Synthesis of the Oxazoline Tetrasaccharide Donor 350
10.3.3.2 Synthesis of Fmoc-GlcNAc-Asn Amino Acid Building Block 351
10.3.3.3 Synthesis of V3 Cyclic GlcNAc Peptide and Endo A Coupling
with Man3GlcNAc Oxazoline Donor 352
References 353
11 Recent Developments in Neoglycopeptide Synthesis 359
Margaret A. Brimble, Nicole Miller, and Geoffrey M. Williams
11.1 Introduction 359
11.2 Neoglycoside and Neoglycopeptide Synthesis 361
11.2.1 S-Glycosides 361
11.2.2 N-Glycosides 362
11.2.3 O-Glycosides 364
11.2.4 C-Glycosides 365
11.2.5 C1⁄4N Linkage 365
11.3 Protein Side-Chain Modifications 366
11.3.1 Modifications of Cysteine Side-Chains 366
11.3.2 Modifications of Lysine Side-Chains 369
11.3.3 Other Side-Chain Modifications 370
11.4 Cu(I)-Catalyzed Azide–Alkyne ‘‘Click’’ Cycloaddition 372
11.4.1 General Aspects of Cu(I)-Catalyzed Azide–Alkyne cycloaddition 372
11.4.2 Neoglycoside and Neoglycopeptide Synthesis via CuAAC 373
11.4.3 CuAAC and Neoglycoproteins 376
11.5 Cross-Metathesis 378
11.6 Application of Neoglycopeptides as
Synthetic Vaccines 380
11.7 Enzymatic, Molecular, and Cell Biological
Techniques 384
11.7.1.1 Enzymatic Glycoprotein Synthesis 385
11.7.2 Molecular and Cell Biological Techniques 385
References 386
Part Three Amino Acids in Combinatorial Synthesis 393
12 Combinatorial/Library Peptide Synthesis 395
Michal Lebl
12.1 Introduction 395
12.2 High-Throughput Synthesis of Peptides 396
12.2.1 Parallel Peptide Synthesis 396
12.2.2 Directed Sorting 400
12.3 Synthesis of Peptide Arrays 402
12.4 Peptide Libraries 406
12.4.1 Synthesis of Peptide Mixtures 406
12.4.2 Synthesis of Peptides on a Mixture of Particles 409
12.4.2.1 Determination of the Structure of a Peptide on an
Individual Bead 416
12.4.3 Solution-Based Screening of OBOC Libraries 418
12.5 Future of Peptide Libraries 421
12.6 Synthetic Protocols 421
12.6.1 Pin Synthesis 421
12.6.2 SPOT Synthesis 422
12.6.3 Synthesis in Tea-Bags 422
12.6.4 Synthesis on Cotton 423
12.6.4.1 Modification of the Cotton Carrier 423
12.6.5 Split-and-Mix Synthesis of OBOC
Noncleavable Libraries 424
12.6.6 Preparation of Dual-Layer Beads 425
12.6.7 Preparation of Library of Libraries 426
12.6.8 Preparation of OBOC Libraries for Testing in
Solution 426
12.6.8.1 Synthesis of Multicleavable Linker 426
12.6.8.2 Synthesis of the Library 428
12.6.8.3 Quality Control of the Doubly Releasable Library 428
12.6.8.4 Two-Stage Release Assay in 96-Well Microassay Plates 429
12.6.9 Synthesis of the Positional Scanning Library 430
12.6.10 Synthesis of the Dual Defined Iterative
Hexapeptide Library 430
12.6.11 Acylation Monitoring by Bromophenol Blue 431
References 432
13 Phage-Displayed Combinatorial Peptides 451
Renhua Huang, Kritika Pershad, Malgorzata Kokoszka,
and Brian K. Kay
13.1 Introduction 451
13.1.1 Types of Phage Vectors 452
13.1.2 Generation of Combinatorial Peptide Libraries 455
13.1.3 Identifying Peptide Ligands to Protein Targets 458
13.1.4 Mapping Protein–Protein Interactions 461
13.1.5 Identifying Peptide Ligands Binding to Cell Surfaces 463
13.1.6 Mapping Protease Specificity 464
13.1.7 Identifying Peptide Ligands to the Surfaces of Inert Materials 464
13.2 Conclusions 465
References 466
14 Designing New Proteins 473
Michael I. Sadowski and James T. MacDonald
14.1 Introduction 473
14.1.1 Why Design New Proteins? 473
14.1.2 How New is ‘‘New?’’ 474
14.2 Protein Design Methods 475
14.2.1 Computational Design 476
14.2.1.1 Computational Enzyme Design 477
14.2.1.2 Results of Computational Design Experiments 478
14.2.2 Directed Evolution Methods 480
14.2.2.1 Randomization Strategies 480
14.2.2.2 Expression Systems and Assays 481
14.2.3 Design of Protein Interfaces 482
14.3 Protocol for Protein Design 484
14.4 Conclusions 486
References 487
15 Amino Acid-Based Dendrimers 491
Zhengshuang Shi, Chunhui Zhou, Zhigang Liu, Filbert Totsingan,
and Neville R. Kallenbach
15.1 Introduction 491
15.2 Peptide Dendrimer Synthesis: Divergent and
Convergent Approaches 491
15.2.1 Synthesis of the First Peptide Dendrimers: Polylysine
Dendrimers 493
15.2.2 Glutamic/Aspartic Acid, Proline, and Arginine Dendrimers 494
15.2.3 Synthesis of MAPs 497
15.2.4 Synthesis of Peptide Dendrimers Grafted on PAMAM and
other Peptide Dendrimers 500
15.3 Applications of Peptide Dendrimers 502
15.3.1 Initial Efforts on MAPs 502
15.3.2 Peptide Dendrimers as Antimicrobial Agents 502
15.3.3 Peptide Dendrimers as Protein/Enzyme Mimics 504
15.3.4 Peptide Dendrimers as Ion Sensors and MRI Contrast Agents 505
15.3.5 Peptide Dendrimers as DNA/RNA Delivery Vectors 507
15.3.6 Other Application of Peptide Dendrimers 512
15.4 Conclusions 513
References 514
Index 519
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