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Searching... | 30000010230355 | RS431.P38 P464 2009 | Open Access Book | Book | Searching... |
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Summary
Summary
Peptides serve as effective drugs in the clinic today. However the inherent drawbacks of peptide structures can limit their efficacy as drugs. To overcome this researchers are developing new methods to create 'tailor-made' peptides and proteins with improved pharmacological properties.
Design of Peptides and Proteins provides an overview of the experimental and computational methods for peptide and protein design, with an emphasis on specific applications for therapeutics and biomedical research. Topics covered include:
Computer modeling of peptides and proteins Peptidomimetics Design and synthesis of cyclic peptides Carbohydrates in peptide and protein design De novo design of peptides and proteins Medical development applications An extended case study - the design of insulin variantsDesign of Peptides and Proteins presents the state-of-the-art of this exciting approach for therapeutics, with contributions from international experts. It is an essential resource for academic and industrial scientists in the fields of peptide and protein drug design, biomedicine, biochemistry, biophysics, molecular modelling, synthetic organic chemistry and medicinal/pharmaceutical chemistry.
Author Notes
Knud J. Jensen, University of Copenhagen, Faculty of Life Sciences, Denmark
Professor Jensen's research interests cover synthetic bioorganic chemistry, peptide chemistry, carbohydrate chemistry, chemical protein synthesis, solid-phase synthesis and glycobiology.
Table of Contents
List of Contributors | p. ix |
Preface | p. xi |
1 Introduction | p. 1 |
2 Computational Approaches in Peptide and Protein Design: An Overview | p. 5 |
2.1 Introduction | p. 5 |
2.2 Basics and Tools | p. 6 |
2.2.1 The Importance of Computational Approaches | p. 6 |
2.2.2 Tools and Procedures: Force Fields and Sampling | p. 9 |
2.3 Computational Study of Cyclopentapeptide Inhibitors of CXCR4 | p. 31 |
2.3.1 The 3D Pharmacophore Model for FC131 | p. 32 |
2.3.2 A 3D Model of the TM Region of CXCR4 | p. 36 |
2.3.3 Docking of FC131 to CXCR4 | p. 39 |
Acknowledgements | p. 42 |
References | p. 42 |
3 Aspects of Peptidomimetics | p. 49 |
3.1 Introduction | p. 49 |
3.2 Modified Peptides | p. 51 |
3.3 Pseudopeptides | p. 65 |
3.4 Secondary Structure Mimics (Excluding Turn Mimics) | p. 75 |
3.4.1 ß-strand Mimetics | p. 75 |
3.4.2 Helix Mimetics | p. 87 |
3.5 Examples of Peptidomimetics | p. 92 |
3.6 Conclusion | p. 104 |
References | p. 105 |
4 Design of Cyclic Peptides | p. 133 |
4.1 Introduction | p. 133 |
4.1.1 Pharmaceutical Research Today | p. 133 |
4.1.2 General Advantages of Cyclic Peptide Structures | p. 134 |
4.1.3 Examples of Cyclic Peptides of Medicinal Interest | p. 135 |
4.1.4 General Considerations | p. 137 |
4.2 Peptide Cyclization | p. 138 |
4.2.1 Possibilities of Peptide Cyclization | p. 138 |
4.2.2 Synthesis of Cyclic Peptides | p. 139 |
4.2.3 Chemical Modifications of Cyclic Peptides | p. 141 |
4.2.4 Concluding Remarks | p. 146 |
4.3 Conformation and Dynamics of Cyclic Peptides | p. 146 |
4.3.1 Reductions in Conformational Space | p. 146 |
4.3.2 Conformational Arrangements in Cyclic Structures | p. 148 |
4.3.3 Flexibility of Cyclized Scaffolds | p. 151 |
4.3.4 Experimental Structure Characterization | p. 152 |
4.4 Concepts in the Rational Design of Cyclic Peptides | p. 154 |
4.4.1 The Influence of Amino Acid Composition | p. 154 |
4.4.2 The Dunitz-Waser Concept | p. 155 |
4.4.3 The Spatial Screening Technique | p. 156 |
4.4.4 General Strategy for Finding Active Hits | p. 157 |
4.5 Examples of Cyclic Peptides as Drug Candidates | p. 159 |
4.5.1 Cilengitide as Integrin Inhibitor | p. 159 |
4.5.2 CXCR4 Antagonists | p. 163 |
4.5.3 Sandostatin and the Veber-Hirschmann Peptide as Examples of Rational Design | p. 164 |
4.6 Conclusion | p. 166 |
References | p. 166 |
5 Carbohydrates in Peptide and Protein Design | p. 177 |
5.1 Introduction | p. 177 |
5.2 Configurational and Conformational Properties of Carbohydrates | p. 178 |
5.3 Carbohydrates in Peptidomimetics | p. 181 |
5.4 Glycopeptides | p. 183 |
5.5 Carbohydrates as Scaffolds in the Design of Nonpeptide Peptidomimetics | p. 185 |
5.6 Sugar Amino Acids | p. 187 |
5.7 Cyclodextrin-Peptide Conjugates | p. 193 |
5.8 Carboproteins: Protein Models on Carbohydrate Templates | p. 198 |
5.9 Conclusion | p. 199 |
References | p. 200 |
6 De Novo Design of Proteins | p. 207 |
6.1 Introduction | p. 207 |
6.2 Secondary Structure Elements | p. 208 |
6.2.1 The ¿-helix | p. 208 |
6.2.2 The ß-sheet | p. 214 |
6.2.3 Loops, Turns and Templates | p. 214 |
6.3 Assembling a Specified Tertiary Structure from Secondary Structural Elements | p. 215 |
6.3.1 Computational Methods | p. 215 |
6.3.2 Coiled Coils | p. 216 |
6.3.3 ¿-helical Bundles | p. 220 |
6.3.4 Fluorous Interactions | p. 225 |
6.3.5 Additional Topics | p. 228 |
6.4 Proteins on Templates | p. 229 |
6.5 Foldamers | p. 234 |
6.6 Biopharmaceutical Applications of De Novo Design | p. 236 |
6.6.1 ¿-helical Structures in Biopharmaceutical Applications | p. 236 |
6.6.2 Foldamers in Biopharmaceutical Applications | p. 238 |
References | p. 238 |
7 Design of Insulin Variants for Improved Treatment of Diabetes | p. 249 |
7.1 Introduction | p. 249 |
7.2 Diabetes Management and the Need for Insulin Engineering | p. 251 |
7.3 Insulin Structure | p. 256 |
7.4 Prolonged-acting Insulin Solids | p. 258 |
7.5 Prolonged-acting Insulin Solutions | p. 259 |
7.6 Fast-acting Insulins | p. 265 |
7.7 Glucose-sensitive Insulin Preparations | p. 267 |
7.8 Alternative Insulin Delivery | p. 271 |
7.9 Insulin Mimetics | p. 272 |
7.10 Pushing the Limits of Insulin Engineering | p. 273 |
7.11 Conclusion | p. 274 |
References | p. 275 |
Index | p. 287 |