Peptide and Protein Design for Biopharmaceutical Applications Book

List of Contributors ix

Preface xi

1 Introduction Knud J. Jensen 1

2 Computational Approaches in Peptide and Protein Design: An Overview Gregory V. Nikiforovicb Garland R. Marshall 5

2.1 Introduction 5

2.2 Basics and Tools 6

2.2.1 The Importance of Computational Approaches 6

2.2.2 Tools and Procedures: Force Fields and Sampling 9

2.3 Computational Study of Cyclopentapeptide Inhibitors of CXCR4 31

2.3.1 The 3D Pharmacophore Model for FC131 32

2.3.2 A 3D Model of the TM Region of CXCR4 36

2.3.3 Docking of FC131 to CXCR4 39

Acknowledgements 42

References 42

3 Aspects of Peptidomimetics Veronique Maes Dirk Tourwé 49

3.1 Introduction 49

3.2 Modified Peptides 51

3.3 Pseudopeptides 65

3.4 Secondary Structure Mimics (Excluding Turn Mimics) 75

3.4.1 β-strand Mimetics 75

3.4.2 Helix Mimetics 87

3.5 Examples of Peptidomimetics 92

3.6 Conclusion 104

References 105

4 Design of Cyclic Peptides Oliver Demmer Andreas O. Frank Horst Kessler 133

4.1 Introduction 133

4.1.1 Pharmaceutical Research Today 133

4.1.2 General Advantages of Cyclic Peptide Structures 134

4.1.3 Examples of Cyclic Peptides of Medicinal Interest 135

4.1.4 General Considerations 137

4.2 Peptide Cyclization 138

4.2.1 Possibilities of Peptide Cyclization 138

4.2.2 Synthesis of Cyclic Peptides 139

4.2.3 Chemical Modifications of Cyclic Peptides 141

4.2.4 Concluding Remarks 146

4.3 Conformation and Dynamics of Cyclic Peptides 146

4.3.1 Reductions in Conformational Space 146

4.3.2 Conformational Arrangements in Cyclic Structures 148

4.3.3 Flexibility of Cyclized Scaffolds 151

4.3.4 Experimental Structure Characterization 152

4.4 Concepts inthe Rational Design of Cyclic Peptides 154

4.4.1 The Influence of Amino Acid Composition 154

4.4.2 The Dunitz-Waser Concept 155

4.4.3 The Spatial Screening Technique 156

4.4.4 General Strategy for Finding Active Hits 157

4.5 Examples of Cyclic Peptides as Drug Candidates 159

4.5.1 Cilengitide as Integrin Inhibitor 159

4.5.2 CXCR4 Antagonists 163

4.5.3 Sandostatin and the Veber-Hirschmann Peptide as Examples of Rational Design 164

4.6 Conclusion 166

References 166

5 Carbohydrates in Peptide and Protein Design Knud J. Jensen Jesper Brask 177

5.1 Introduction 177

5.2 Configurational and Conformational Properties of Carbohydrates 178

5.3 Carbohydrates in Peptidomimetics 181

5.4 Glycopeptides 183

5.5 Carbohydrates as Scaffolds in the Design of Nonpeptide Peptidomimetics 185

5.6 Sugar Amino Acids 187

5.7 Cyclodextrin-Peptide Conjugates 193

5.8 Carboproteins: Protein Models on Carbohydrate Templates 198

5.9 Conclusion 199

References 200

6 De Novo Design of Proteins Knud J. Jensen 207

6.1 Introduction 207

6.2 Secondary Structure Elements 208

6.2.1 The α-helix 208

6.2.2 The β-sheet 214

6.2.3 Loops, Turns and Templates 214

6.3 Assembling a Specified Tertiary Structure from Secondary Structural Elements 215

6.3.1 Computational Methods 215

6.3.2 Coiled Coils 216

6.3.3 α-helical Bundles 220

6.3.4 Fluorous Interactions 225

6.3.5 Additional Topics 228

6.4 Proteins on Templates 229

6.5 Foldamers 234

6.6 Biopharmaceutical Applications of De Novo Design 236

6.6.1 α-helical Structures in Biopharmaceutical Applications 236

6.6.2 Foldamers in Biopharmaceutical Applications 238

References 238

7 Design of Insulin Variants for Improved Treatment of Diabetes Thomas Hoeg-Jensen 249

7.1 Introduction 249

7.2 Diabetes Management and the Need for Insulin Engineering 251

7.3 Insulin Structure 256

7.4 Prolonged-acting Insulin Solids 258

7.5 Prolonged-acting Insulin Solutions 259

7.6 Fast-acting Insulins 265

7.7 Glucose-sensitive Insulin Preparations 267

7.8 Alternative Insulin Delivery 271

7.9 Insulin Mimetics 272

7.10 Pushing the Limits of Insulin Engineering 273

7.11 Conclusion 274

References 275

Index 287