Chemical Approaches to the Synthesis of Peptides and Proteins

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ISBN: 9780849391422 | 0849391423
Cover: Hardcover
Copyright: 4/23/1997

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Organic chemists working on the synthesis of natural products have long found a special challenge in the preparation of peptides and proteins. However, more reliable, more efficient synthetic preparation methods have been developed in recent years. This reference evaluates the most important synthesis methods available today, and also considers methods that show promise for future applications.This text describes the state of the art in efficient synthetic methods for the synthesis of both natural and artificial large peptide and protein molecules. Subjects include an introduction to basic topics, linear solid-phase synthesis of peptides, peptide synthesis in solution, convergent solid-phase synthesis, methods for the synthesis of branched peptides, formation of disulfide bridges, and more. The book emphasizes strategies and tactics that must be considered for the successful synthesis of peptides.

Chapter 1 Introduction

(18)

1.1 Amino Acids and Peptide and Protein Structure

(1)

1.2 Amino Acids Activation and Coupling

(4)

1.2.1 Acid Azides, Acid Halides, and Anhydrides

(1)

1.2.2 Active Esters

(1)

1.2.3 Coupling Reagents

(1)

1.3 Protection Schemes for Peptide Synthesis

(4)

1.3.1 NXXX Protection

(1)

1.3.2 Side Chain Protection

(1)

1.3.3 Protection of the C-Terminus

(1)

1.3.4 Compatibility of Protecting Groups -- Orthogonality

(1)

1.4 Synthesis of Peptides

(4)

1.4.1 Synthesis in Solution

(1)

1.4.2 Solid-Phase Peptide Synthesis

(2)

1.4.3 SPPS vs. Synthesis in Solution

(1)

References

(3)

Chapter 2 Solid-Phase Peptide Synthesis

(76)

2.1 The Solid Support

(2)

2.1.1 Cross-Linked Polystyrene

(1)

2.1.2 Polyamide

(1)

2.1.3 Polyethylene Glycol-Grafted Polystyrene

(1)

2.2 Protection Schemes

(20)

2.2.1 NXXX Protection

(2)

2.2.2 Side Chain Protection of Individual Amino Acids

(18)

2.2.2.1 Lysine and Ornithine

(2)

2.2.2.2 Arginine

(2)

2.2.2.3 Histidine

(3)

2.2.2.4 Tryptophan

(1)

2.2.2.5 Asparagine and Glutamine

(1)

2.2.2.6 Aspartic and Glutamic Acids

(2)

2.2.2.7 Serine and Threonine

(1)

2.2.2.8 Tyrosine

(1)

2.2.2.9 Methionine

(2)

2.2.2.10 Cysteine

(2)

2.3 Attachment of the First Amino Acid to the Solid Support

(7)

2.3.1 Peptide Acids

(3)

2.3.2 Peptide Amides

(1)

2.3.3 Side Chain and Backbone Amide Anchoring

(2)

2.4 Chain Elongation

(23)

2.4.1 Amino Acid Coupling

(11)

2.4.1.1 Carbodiimides

(5)

2.4.1.2 Phosphonium and Uronium Reagents

(2)

2.4.1.3 Preformed Active Esters

(1)

2.4.1.4 Preformed Anhydrides

(2)

2.4.1.5 Amino Acid Halides

(1)

2.4.2 Problems during Chain Elongation

(8)

2.4.2.1 Undesired Cyclizations

(1)

2.4.2.1.1 Formation of Diketopiperazines

(2)

2.4.2.1.2 Formation of Aspartimides

(2)

2.4.2.1.3 Formation of Pyroglutamic Acid

(1)

2.4.2.2 Incomplete NXXX Deprotection and Amino Acid Coupling Reactions

(1)

2.4.2.2.1 Deletion Peptides and Truncated Sequences

(1)

2.4.2.2.2 Difficult Sequences

(2)

2.4.2.3 Other Problems in Chain Assembly

(1)

2.4.3 On-Resin Monitoring of SPPS

(4)

2.4.3.1 Peptide-Resin Mass

(1)

2.4.3.2 The Ninhydrin Test

(1)

2.4.3.3 Amino Acid Analysis

(1)

2.4.3.4 Solid-Phase Edman Degradation

(1)

2.5 Cleavage of the Peptide from the Resin

(4)

2.5.1 Acidolysis

(1)

2.5.1.1 Liquid Hydrogen Fluoride

(1)

2.5.1.2 Trifluoroacetic Acid

(1)

2.5.2 Side Reactions during Acidolytic Cleavage of Peptides from the Solid Support

(3)

2.5.2.1 Alkylation

(1)

2.5.2.2 Undesired Cyclization Reactions

(1)

2.5.2.3 Other Side Reactions during Acidolytic Cleavage

(1)

2.6 Examples of Protein Synthesis by Linear SPPS

(7)

2.6.1 Bovine Pancreatic Ribonuclease A

(2)

2.6.2 Human Immunodeficiency Virus Protease

(2)

2.6.3 Ubiquitin

(2)

2.6.4 XXX-Amyloid Protein

(2)

References

(13)

Chapter 3 Peptide Synthesis in Solution

(44)

3.1 Strategic Considerations

(1)

3.2 Protection Schemes

(9)

3.2.1 NXXX Protection

(2)

3.2.2 Side Chain Protection of Amino Acids

(1)

3.2.3 Protection of the C-Terminus

(6)

3.2.3.1 Alkyl and Aryl Esters

100

(4)

3.2.3.1.1 Benzyl and Substituted Benzyl Esters

100

(1)

3.2.3.1.2 Phenacyl Esters

101

(1)

3.2.3.1.3 tert-Butyl Esters

102

(1)

3.2.3.1.4 Methyl and Substituted Methyl Esters

102

(1)

3.2.3.1.5 Ethyl and Substituted Ethyl Esters

103

(1)

3.2.3.1.6 Phenyl Esters

103

(1)

3.2.3.2 Hydrazides

104

(1)

3.3 Chain Elongation

105

(17)

3.3.1 Amino Acid Coupling

105

(9)

3.3.1.1 Acyl Azides

106

(1)

3.3.1.2 Anhydrides

106

(1)

3.3.1.2.1 Mixed Carboxylic Acid Anhydrides

106

(1)

3.3.1.2.2 Mixed Carbonic Acid Anhydrides

107

(1)

3.3.1.2.3 N-Carboxyanhydrides and Urethane N-Protected Carboxyanhydrides

108

(1)

3.3.1.2.4 Mixed Anhydrides with Acids Derived from Phosphorus

109

(1)

3.3.1.2.5 NXXX Protected Amino Acid Symmetrical Anhydrides

110

(1)

3.3.1.3 Active Esters

110

(1)

3.3.1.4 Carbodiimides

111

(1)

3.3.1.5 Phosphonium and Uronium Reagents

112

(1)

3.3.1.6 Acyl Halides

113

(1)

3.3.2 Peptide-Segment Coupling

114

(7)

3.3.2.1 Racemization and Epimerization in Peptide Synthesis

114

(5)

3.3.2.1.1 Direct Enolization

115

(1)

3.3.2.1.2 Formation and Epimerization of 5(4H)-Oxazolones

116

(1)

3.3.2.1.3 Acid-Catalyzed Racemization

119

(1)

3.3.2.2 Suppression of Racemization in the Coupling of Peptide Segments

119

(2)

3.3.2.2.1 Glycine and Proline as C-Terminal Amino Acids

119

(1)

3.3.2.2.2 Coupling Methods that Proceed with Minimal Racemization

120

(1)

3.3.3 Side Reactions during Chain Elongation

121

(1)

3.3.3.1 Diketopiperazine Formation

122

(1)

3.3.3.2 Hydantoin Formation

122

(1)

3.4 Final Removal of Protecting Groups

122

(1)

3.5 Special Approaches to the Synthesis of Peptides in Solution

123

(3)

3.5.1 Use of Picolyl Ester-Protecting Groups

123

(1)

3.5.2 Rapid Synthesis in Solution

124

(1)

3.5.2.1 Repetitive Mixed Anhydride Approach

124

(1)

3.5.2.2 Bodanszky's Reactor

125

(1)

3.5.2.3 Rapid Continuous Peptide Synthesis

125

(1)

3.5.3 Liquid-Phase Peptide Synthesis

125

(1)

3.6 Examples of Peptide Synthesis in Solution

126

(4)

3.6.1 Porcine Gastrin I

126

(1)

3.6.2 Human Parathyroid Hormone

127

(1)

3.6.3 Bovine Pancreatic Ribonuclease A

127

(3)

References

130

(9)

Chapter 4 Convergent Approaches to the Synthesis of Large Peptides and Proteins

139

(70)

4.1 Convergent Solid-Phase Peptide Synthesis

140

(24)

4.1.1 Solid-Phase Synthesis of Protected Peptide Segments

141

(7)

4.1.1.1 Acidolytic Cleavage of Protected Peptides from the Solid Support

141

(2)

4.1.1.1.1 Highly Acid-Labile Handles and Resins

142

(1)

4.1.1.1.2 The Wang Resin

143

(3)

4.1.1.2 Nucleophile-and Base-Mediated Cleavage of Protected Peptides from the Solid Support

144

(1)

4.1.1.2.1 The Kaiser Oxime Resin

144

(1)

4.1.1.2.2 Cleavage of the Peptide-Resin Anchorage by a XXX-Elimination Reaction

145

(1)

4.1.1.2.3 Miscellaneous Methods

146

(1)

4.1.1.3 Photolytic Cleavage of Protected Peptides from the Solid Support

146

(2)

4.1.1.3.1 Nitrobenzyl Resins

146

(1)

4.1.1.3.2 Phenacyl Resins

147

(1)

4.1.1.4 Cleavage of Protected Peptides from Allyl-Functionalized Resins

148

(1)

4.1.2 Purification of Protected Peptide Segments

148

(5)

4.1.2.1 Enhancement of the Solubility of Protected Peptide Segments

149

(2)

4.1.2.1.1 Structural Modification

149

(1)

4.1.2.1.2 Use of Special Solvents or Additives to Enhance Solubility

150

(1)

4.1.2.2 Purification Methods

151

(2)

4.1.2.2.1 Gel Filtration

151

(1)

4.1.2.2.2 Reversed-Phase High-Performance Liquid Chromatography

151

(2)

4.1.2.3 Determination of Covalent Structure

153

(1)

4.1.3 Solid-Phase Coupling of Protected Peptide Segments

153

(1)

4.1.3.1 The Solid Support

153

(1)

4.1.3.2 Synthesis Strategy

154

(1)

4.1.3.3 Incorporation of the First Segment

154

(1)

4.1.3.4 Coupling Methods

155

(1)

4.1.3.5 Side Reactions

155

(1)

4.1.3.6 Monitoring of the Coupling Reaction

156

(1)

4.1.4 Examples of Convergent Solid-Phase Peptide Synthesis

156

(8)

4.1.4.1 Rat Atrial Natriuretic Factor

156

(1)

4.1.4.2 Prothymosin XXX

157

(1)

4.1.4.3 XXX-Amyloid Protein

158

(2)

4.1.4.4 The 3-Repeat Region of Human Tau-2

160

(2)

4.1.4.5 The N-Terminal Repeat Region of XXX-Zein

162

(2)

4.2 Coupling of Protected Peptide Segments in Solution

164

(1)

4.2.1 Lipophilic Segment Coupling Strategy

164

(1)

4.3 Coupling of Minimally Protected Peptides in Aqueous Solution

165

(10)

4.3.1 Activation of C-Terminal Thiocarboxyl or Thioester Groups

166

(9)

4.3.1.1 Examples of Synthesis Using C-Terminus Thiocarboxyl or Thioester Activation

170

(5)

4.3.1.1.1 Bovine [Cys(Cam)(14,17)]-Apocytochrome C

170

(2)

4.3.1.1.2 XXX-Inhibin-92

172

(2)

4.3.1.1.3 DNA-Binding Protein of Bacillus 174 stearothermophilus

174

(1)

4.4 Chemical Ligation of Peptide Segments

175

(25)

4.4.1 Chemical Ligation to Give Backbone-Engineered Protein Analogues

176

(8)

4.4.1.1 Chemical Ligation by Thioester or Thioether Formation

176

(5)

4.4.1.2 Chemical Ligation by Hydrazone or Oxime Formation

181

(3)

4.4.1.3 Use of More than One Type of Chemical Ligation for Protein Analogue Synthesis

184

(1)

4.4.2 Segment Coupling by Prior Chemical Ligation

184

(11)

4.4.2.1 Template-Assisted Coupling

186

(4)

4.4.2.2 Native Chemical Ligation

190

(1)

4.4.2.3 Domain Ligation

191

(4)

4.4.3 Chemical Ligation for the Synthesis of Branched Artificial Proteins

195

(5)

4.4.3.1 Multiple Antigenic Peptides

195

(2)

4.4.3.2 Template-Assembled Synthetic Proteins

197

(3)

References

200

(9)

Chapter 5 Formation of Disulfide Bridges

209

(28)

5.1 Peptides with Disulfide Bridges

210

(1)

5.1.1 Intramolecular Disulfide Bridges

210

(1)

5.1.2 Intermolecular Disulfide Bridges

210

(1)

5.2 Protection of Cysteine in Peptide Synthesis

211

(3)

5.3 Chemical Methods for the Formation of Disulfide Bridges

214

(9)

5.3.1 From Precursors with Free Sulfhydryl Groups

214

(3)

5.3.2 From Precursors with Protected Sulfhydryl Groups

217

(2)

5.3.3 Directed Disulfide Bridge Formation

219

(4)

5.3.3.1 Selective Activation of Cysteine Residues In Situ

219

(1)

5.3.3.2 Selective Activation that Gives a Stable, Isolable Intermediate

220

(2)

5.3.3.3 Use of the S-3-Nitro-2-Pyridinesulfenyl Group

222

(1)

5.3.4 From Cystine

223

(1)

5.4 Regioselective Disulfide Bridge Formation

223

(8)

5.4.1 Intramolecular Disulfide Bridges

223

(4)

5.4.2 Intermolecular Disulfide Bridges

227

(4)

5.4.2.1 Preparation of Parallel and Antiparallel Homodimers Linked by Two Disulfide Bridges

227

(1)

5.4.2.2 Insulin and Related Peptides

228

(3)

References

231

(6)

Chapter 6 Peptide Libraries

237

(34)

6.1 Multiple-Peptide Synthesis in Parallel

238

(8)

6.1.1 Peptide Synthesis on Polyethylene Pins

238

(4)

6.1.2 Peptide Synthesis in Tea Bags

242

(1)

6.1.3 Peptide Synthesis on Special Solid Supports

243

(1)

6.1.4 Light-Directed, Spatially Addressable Parallel Peptide Synthesis

244

(1)

6.2 Peptide Library Techniques

246

(19)

6.2.1 Synthesis of Peptide Libraries by Coupling Mixtures of Amino Acids

247

(1)

6.2.2 Synthesis of Peptide Libraries by the Split-and-Combine Method

248

(1)

6.2.3 Peptide Library Deconvolution

249

(4)

6.2.3.1 The Dual-Defined Method

250

(1)

6.2.3.2 The Positional Scanning Method

251

(1)

6.2.3.3 The Bogus Coin Method

252

(1)

6.2.4 One-Bead/One-Peptide Libraries

253

(8)

6.2.4.1 Screening of One-Bead/One-Peptide Libraries in Solution

255

(2)

6.2.4.2 Encoded Combinatorial Peptide Synthesis

257

(4)

6.2.4.2.1 Library Encoding with Oligonucleotides

258

(1)

6.2.4.2.2 Library Encoding with Peptides

259

(1)

6.2.4.2.3 Library Encoding with Aryl Halide Tags

260

(1)

6.2.4.2.4 Radio Frequency Encoding

261

(1)

6.2.5 Quality Control

261

(2)

6.2.5.1 Amino Acid Analysis and Edman Sequencing

262

(1)

6.2.5.2 Mass Spectrometry

262

(1)

6.2.5.3 Other Techniques

262

(1)

6.2.6 Screening

263

(2)

6.2.6.1 Screening Libraries of Immobilized Peptides

263

(1)

6.2.6.2 Screening of Peptide Libraries in Solution

264

(1)

6.3 Examples of Peptide Library Synthesis

265

(3)

6.3.1 An All D-Amino Acid Opioid Peptide

265

(1)

6.3.2 Novel Ligands for the SH3 Domain of Phosphatidylinositol 3-Kinase

266

(1)

6.3.3 Sequence-Selective Peptide Binding with a Peptido-Steroidal Receptor

267

(1)

References

268

(3)

Index

271

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Chemical Approaches to the Synthesis of Peptides and Proteins

Summary

Table of Contents

Supplemental Materials

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Chemical Approaches to the Synthesis of Peptides and Proteins

Summary

Table of Contents

Supplemental Materials

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