Biologically Active Peptides: Design, Synthesis, and Utilization

Transcription

1 -BIOMEDICAL APPLICATIONS OF BIOTECHNOLOGY- VOLUME 1 Biologically Active Peptides: Design, Synthesis, and Utilization EDITED BY William V. Williams, M.D. Director of Rheumatology Research University of Pennsylvania David B. Weiner, Ph.D. Director of Biotechnology The Wistar Institute TECHNOMIC.PUBLISHING CO., INC T ANCASTER BASET,

2 Introduction ix Section I: Structural Approaches to Peptide Design 1. STRATEGIES IN PROTEIN-BASED RATIONAL DRUG DESIGN 3 THOMAS KIEBER-EMMONS Introduction 3 Theory and Methodology 4 Antibodies as Biosyhthetic Templates 10 Bioactive Peptide Design and Active Site Structure 16 Future Directions 25 References COMPUTER ASSISTED DESIGN OF PEPTIDOMIMETIC DRUGS 35 VIDUKUDI N. BALAJI and KALYANARAMAN RAMNARAYAN Summary 35 Introduction 35 Approaches to Peptidomimetic Design 38 Acknowledgements 50 References BIOACTIVE PEPTIDE DESIGN BASED ON ANTIBODY STRUCTURE 55 JOAN M. VON FELDT, KENNETH E. UGEN, THOMAS KIEBER-EMMONS, and WILLIAM V. WILLIAMS

3 vi Antibodies: A Natural Pharmacologic Model 55 Immunoglobulin Genetics and Structure 56 Strategies for Antibody-Based Peptide Design 68 Peptide Evaluation 76 Summary 79 Acknowledgements 80 References NMR SPECTROSCOPY OF PEPTIDES AND PROTEINS IN MEMBRANE ENVIRONMENTS 87 KI-JOON SHON and STANLEY J. OPELLA Introduction 87 NMR Spectroscopy of Membrane Proteins in Micelles 88 NMR Spectroscopy of Membrane Peptides in Bilayers 96 Application of Combined NMR Methods to a Membrane Protein 102 Summary 108 Acknowledgements 108 References 108 Section II: Chemical Synthetic Aspects of Peptide Production 5. LARGE SCALE PEPTIDE PRODUCTION 113 MARIA-LUISA MACCECCHINI Summary 113 Introduction 113 Peptide Synthesis 115 Scale Up 123 Purification 127 Automation 129 Conclusions 130 Abbreviations 131 Acknowledgements 132 Appendix 132 References ADVANCES IN PEPTIDE SYNTHESIS 135 MOHMED K. ANWER and SHABBIR A. KHAN Protection of the Reactive Functional Groups 136 Coupling Methods: Formation of the Peptide Bond 138 Deprotection Methods 141 Solid-Phase Synthesis of Peptides 144

4 vii Peptide Mimetics 147 Acknowledgements 148 References DEVELOPMENT OF CHEMICALLY MODIFIED PEPTIDES 155 LASZLO OTVOS, JR. and MIKLOS HOLLOSI Overview 155 Chemical Synthesis of Glycopeptides 158 Chemical Synthesis of Phosphopeptides 172 Summary and Future Trends 176 Abbreviations 176 Acknowledgements 179 References DESIGN AND SYNTHESIS OF BIOLOGICALLY ACTIVE PEPTIDE MIMICS 187 ROBERT M. WILLIAMS Introduction 187 Pepstatin 187 Fluoro Ketones 195 Hydroxyethylene Isosteres 197 HIV Protease Inhibitors 204 Inverted Amines 209 Phosphorous Analogs 210 Abbreviations 212 References 213 Section III: Utilization of Bioactive Peptides 9. SYNTHETIC PEPTIDE-BASED VACCINES AND ANTIVIRAL AGENTS INCLUDING HIV/AIDS AS A MODEL SYSTEM 219 DAVID N. LEVY and DAVID B. WEINER Introduction 219 The Immune Response 220 Why Peptides? 222 Peptides as Antigens and Immunogens 224 B Cell Responses 229 T Cell Responses 241 Peptides as Viral Antagonists 247 Conclusion 251 References 252

5 viii 10. PEPTIDES AS MOLECULAR PROBES OF IMMUNE RESPONSES 269 ELLEN HEBER-KATZ and HILDEGUND C. J. ERTL Introduction 269 Definition of Immunodominance 269 The Role of Peptide Structure in T Cell Responses 279 Protection from Viral Infections by Peptide Vaccines 283 Conclusion 284 Acknowledgements 285 References THE DESIGN OF MHC BINDING PEPTIDES 289 ALESSANDRO SETTE, ALAN G. LAMONT, and HOWARD M. GREY Introduction 289 Structural Features of High Affinity MHC Binders 290 Structural Modifications of MHC Binding Peptides 291 Peptide Modifications and Biological Activity 299 Conclusions 302 References BIOLOGY AND CHEMISTRY OF EXTRACELLULAR MATRIX CELL ATTACHMENT PEPTIDES 307 FRANK A. ROBEY Introduction 307 Components and Peptides from Extracellular Matrices 308 Conjugates and Uses of Peptides from Extracellular Matrix 313 Experimental Metastasis 316 Future Applications of Peptides Derived from Extracellular Matrix Proteins 317 References DESIGN OF PEPTIDE ANALOG INHIBITORS OF PROTEOLYTIC PROCESSES 325 STEPHAN K. GRANT, THOMAS D. MEEK, BRIAN W. METCALF, and STEPHEN R. PETTEWAY, JR. Introduction 325 Specificity and Catalytic Mechanisms of Proteases 327 Peptide Analog Inhibitors of ACE 330 Renin Peptide Analog Inhibitors 336 HIV-1 Protease Peptide Analog Inhibitors 342 References 346 Index 355