Chemical Approaches to the Synthesis of Peptides and Proteins,9780849391422

Chemical Approaches to the Synthesis of Peptides and Proteins

by ;
Edition: 1st
ISBN13: 9780849391422
ISBN10: 0849391423
Format: Hardcover
Pub. Date: 1997-04-23
Publisher(s): CRC Press
List Price: $272.84

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Summary

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.

Table of Contents

Chapter 1 Introduction
1(18)
1.1 Amino Acids and Peptide and Protein Structure
3(1)
1.2 Amino Acids Activation and Coupling
4(4)
1.2.1 Acid Azides, Acid Halides, and Anhydrides
6(1)
1.2.2 Active Esters
7(1)
1.2.3 Coupling Reagents
7(1)
1.3 Protection Schemes for Peptide Synthesis
8(4)
1.3.1 NXXX Protection
10(1)
1.3.2 Side Chain Protection
11(1)
1.3.3 Protection of the C-Terminus
11(1)
1.3.4 Compatibility of Protecting Groups -- Orthogonality
12(1)
1.4 Synthesis of Peptides
12(4)
1.4.1 Synthesis in Solution
12(1)
1.4.2 Solid-Phase Peptide Synthesis
13(2)
1.4.3 SPPS vs. Synthesis in Solution
15(1)
References
16(3)
Chapter 2 Solid-Phase Peptide Synthesis
19(76)
2.1 The Solid Support
19(2)
2.1.1 Cross-Linked Polystyrene
20(1)
2.1.2 Polyamide
20(1)
2.1.3 Polyethylene Glycol-Grafted Polystyrene
21(1)
2.2 Protection Schemes
21(20)
2.2.1 NXXX Protection
21(2)
2.2.2 Side Chain Protection of Individual Amino Acids
23(18)
2.2.2.1 Lysine and Ornithine
24(2)
2.2.2.2 Arginine
26(2)
2.2.2.3 Histidine
28(3)
2.2.2.4 Tryptophan
31(1)
2.2.2.5 Asparagine and Glutamine
32(1)
2.2.2.6 Aspartic and Glutamic Acids
33(2)
2.2.2.7 Serine and Threonine
35(1)
2.2.2.8 Tyrosine
36(1)
2.2.2.9 Methionine
37(2)
2.2.2.10 Cysteine
39(2)
2.3 Attachment of the First Amino Acid to the Solid Support
41(7)
2.3.1 Peptide Acids
42(3)
2.3.2 Peptide Amides
45(1)
2.3.3 Side Chain and Backbone Amide Anchoring
46(2)
2.4 Chain Elongation
48(23)
2.4.1 Amino Acid Coupling
48(11)
2.4.1.1 Carbodiimides
48(5)
2.4.1.2 Phosphonium and Uronium Reagents
53(2)
2.4.1.3 Preformed Active Esters
55(1)
2.4.1.4 Preformed Anhydrides
56(2)
2.4.1.5 Amino Acid Halides
58(1)
2.4.2 Problems during Chain Elongation
59(8)
2.4.2.1 Undesired Cyclizations
59(1)
2.4.2.1.1 Formation of Diketopiperazines
59(2)
2.4.2.1.2 Formation of Aspartimides
61(2)
2.4.2.1.3 Formation of Pyroglutamic Acid
63(1)
2.4.2.2 Incomplete NXXX Deprotection and Amino Acid Coupling Reactions
64(1)
2.4.2.2.1 Deletion Peptides and Truncated Sequences
64(1)
2.4.2.2.2 Difficult Sequences
65(2)
2.4.2.3 Other Problems in Chain Assembly
67(1)
2.4.3 On-Resin Monitoring of SPPS
67(4)
2.4.3.1 Peptide-Resin Mass
68(1)
2.4.3.2 The Ninhydrin Test
68(1)
2.4.3.3 Amino Acid Analysis
69(1)
2.4.3.4 Solid-Phase Edman Degradation
70(1)
2.5 Cleavage of the Peptide from the Resin
71(4)
2.5.1 Acidolysis
71(1)
2.5.1.1 Liquid Hydrogen Fluoride
71(1)
2.5.1.2 Trifluoroacetic Acid
72(1)
2.5.2 Side Reactions during Acidolytic Cleavage of Peptides from the Solid Support
72(3)
2.5.2.1 Alkylation
72(1)
2.5.2.2 Undesired Cyclization Reactions
73(1)
2.5.2.3 Other Side Reactions during Acidolytic Cleavage
74(1)
2.6 Examples of Protein Synthesis by Linear SPPS
75(7)
2.6.1 Bovine Pancreatic Ribonuclease A
75(2)
2.6.2 Human Immunodeficiency Virus Protease
77(2)
2.6.3 Ubiquitin
79(2)
2.6.4 XXX-Amyloid Protein
80(2)
References
82(13)
Chapter 3 Peptide Synthesis in Solution
95(44)
3.1 Strategic Considerations
95(1)
3.2 Protection Schemes
96(9)
3.2.1 NXXX Protection
97(2)
3.2.2 Side Chain Protection of Amino Acids
99(1)
3.2.3 Protection of the C-Terminus
99(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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