Protein design and the development of new therapeutics and vaccines
著者
書誌事項
Protein design and the development of new therapeutics and vaccines
（New horizons in therapeutics）
Plenum Press, c1990
大学図書館所蔵 全1件
注記
Based on a symposium held in Nov. 1988 in King of Prussia, Penn., sponsored by Smith, Kline, & French
Includes bibliographical references and index
内容説明・目次
目次
I. Advances in the Structural Analysis of Proteins.- 1 Dynamic Processes in Proteins by X-Ray Diffraction.- 1. Dynamic Processes in Proteins.- 2. Enzyme Substrate Complexes by X-Ray Diffraction.- 3. Laue Diffraction.- 4. Reaction Synchronization.- References.- 2 Mass Spectrometric Methods for Determination of the Structure of Peptides and Proteins.- 1. Introduction.- 2. High-Mass Mass Spectrometry.- 3. Tandem Mass Spectrometry.- 3.1. Sequencing of Proteins.- 3.2. Increasing Sensitivity by Using an Array Detector.- 3.3. Computer-Aided Interpretation of CID Spectra of Peptides.- 4. Conclusion.- References.- II. Protein Folding and Stability.- 3 Protein Folding and Stability.- 1. Goals.- 2. Folding of Fragments.- 3. Trapping Folding Intermediates.- References.- 4 Genetic Analysis of Polypeptide Chain Folding and Misfolding in Vivo.- 1. Introduction.- 2. The Protein Folding Grammar.- 3. Intracellular Intermediates in Chain Folding and Assembly.- 4. Temperature-Sensitive Folding Mutations.- 5. Nonsense Mutations.- 6. Intracellular Aggregation and Inclusion Body Formation.- 7. Kinetics of Aggregate Formation.- 8. Isolation of Second-Site Suppressors of Folding Mutants.- 9. The Suppressing Amino Acid Substitutions Act at the Level of Polypeptide Chain Maturation.- 10. The Suppressors Act in the Folding of the Single Chain, Not during Chain-Chain Association.- 11. The Suppressors Increase the Efficiency of Folding of the Wild-Type Chain.- References.- 5 Unfolding and Inactivation: Genetic and Chemical Approaches to the Stabilization of T4 Lysozyme and Human Interferon Gamma against Irreversible Thermal Denaturation.- 1. Introduction.- 2. T4 Lysozyme.- 2.1. Sulfhydryl Oxidation.- 2.2. Thiol/Disulfide Interchange.- 2.3. Adsorption.- 2.4. Aggregation.- 2.5. Chemical Inactivation.- 2.6. Conclusions from T4 Lysozyme Experiments.- 3. Interferon-?.- 3.1. In Vitro Experiments.- 3.2. Genetic Experiments.- 4. General Conclusions.- 4.1. Modes of Thermal-Irreversible Denaturation.- 4.2. Strategies for Stabilizing Proteins.- References.- III. Principles of Receptor Design and Regulation.- 6 Protein-Tyrosine Kinases and Their Substrates: Old Friends and New Faces.- 1. Introduction.- 2. Isolation of Novel Protein-Tyrosine Kinases.- 3. Regulation of Protein-Tyrosine Kinase Activity: Phosphorylation of pp60c-src.- 4. Protein-Tyrosine Kinase Substrates.- References.- IV. The Guanine Nucleotide Binding Protein Family.- 7 G Proteins: A Family of Signal-Transducing Molecules.- 1. The Family of G Proteins.- 2. Distribution of G Protein ? Subunits.- 3. Regulation of ?o Levels.- 4. G Proteins as Bifurcating Signals.- 5. Organizing Principles.- References.- 8 Model of Signal Transduction by G Proteins: Roles of a Subunits and ?? Dimers in Regulation of Ionic Channels and Adenylyl Cyclase.- 1. Introduction.- 2. Mechanisms of Receptor-Mediated Activation of G Proteins.- 3. Which G-Protein Subunit Mediates the Effect of Receptors?.- 3.1. Regulation of Ionic Channels: ? or ??, and What Does Each Do to Regulation of Channel Activity?.- 3.2. Inhibitory Regulation of Adenylyl Cyclase: ?i or ???.- 3.3. What Is the Role of ?? Dimers?.- References.- 9 Structural Homologies in G-Binding Proteins.- 1. Introduction.- 2. Structural Homology in Three Dimensions.- 2.1. Elongation Factor Tu (EF-Tu).- 2.2. ras Protein p21.- 3. Sequence Homology.- 3.1. Overall Homology.- 3.2. Consensus Sequences.- 4. Homology and Functional Similarity.- References.- V. Modeling and Structure Prediction in Macromolecules.- 10 Knowledge-Based Protein Modeling and the Design of Novel Molecules.- 1. Introduction.- 2. Learning by Comparison of Structures.- 2.1. Superposition of Structures.- 2.2. Comparison of Properties and Relations.- 2.3. Clustering and Tree Construction.- 3. Rules for Tertiary Templates and Key Residues, and Their Comparison with a Sequence of an Unknown.- 3.1 Consensus Sequences for Framework Regions.- 3.2. Key Residues from Comparisons of Properties and Relations.- 3.3. Characteristic Sequences from Features of Tertiary Structure.- 4. Generation of a Model from a Sequence of an Unknown Using Rules from Comparison of Structures.- 4.1. Construction of the Model by Assembly of Rigid Groups in Three Dimensions.- 4.2. Construction of a Model Using Optimization Techniques.- 4.3. Refinement of the Model.- 5. Applications to Design of Novel Molecules.- 5.1. Receptor-Based Drug Design.- 5.2. Site-Directed Mutagenesis.- 5.3. Chimeric Molecules.- 5.4. Ab Initio Protein Design.- References.- 11 Computer Simulation Methods as Applied to Site-Specific Mutations.- 1. Introduction.- 2. Methodology.- 3. Applications of Molecular Dynamics/Free-Energy Calculations to Site-Specific Mutagenesis.- 3.1. Structure Correlation with X-Ray Observations.- 3.2. Free Energies of Solvation and Ligand Binding.- 3.3. Free Energies of Binding and Catalysis of Site-Specific Mutants.- 3.4. Free Energies of Protein Stability.- 4. Summary and Critique.- References.- 12 Dihydrofolate Reductase: A Paradigm for Drug Design.- 1. Introduction.- 2. Structure and Kinetics of Dihydrofolate Reductase from E. coli.- 2.1. Structure.- 2.2. Kinetics.- 3. Mutagenesis Studies.- 3.1. Ligand Binding and Catalytic Turnover.- 3.2. Long-Range Effects.- 3.3. Nonconserved Residues.- 4. Conclusions.- References.- VI. Protein Engineering and Enzyme Design.- 13 Chemical Approaches to Protein Engineering.- 1. Introduction.- 2. Types of Chemical Approach.- 2.1. Total Synthesis.- 2.2. Side-Chain Modification.- 3. Semisynthesis.- 3.1. Noncovalent Semisynthesis.- 3.2. Covalent Semisynthesis: Disulfide Bridges.- 3.3. Covalent Semisynthesis: The Peptide Bond.- 4. Recent Advances in Knowledge Achieved with Semisynthetic Proteins.- 4.1. Insulin.- 4.2. Other Hormones.- 4.3. Cytochrome c.- 4.4. Hemoglobins.- 4.5. Phospholipase A2.- 5. Linkages Other than by Peptide Bonds.- 5.1. Linkages at the Amino Terminus.- 5.2. Linkages at the Carboxyl Terminus.- 6. Conclusions.- References.- 14 New Engineered Proteins for Use in Therapy and Vaccine Design.- 1. Introduction.- 2. New Generation of Factor VIII Molecules for the Treatment of Hemophilia A.- 3. Hirudin: Variants with Improved Antithrombic Activity.- 4. ?1-Antitrypsin.- 5. HIV Envelope Protein: Improved Antigenicity by Cleavage Site Removal.- References.- 15 Receptor-Based Design of Dihydrofolate Reductase Inhibitors.- 1. Introduction.- 2. The Enzyme.- 2.1. Role in Cellular Metabolism.- 2.2. Primary Structure.- 2.3. Three-Dimensional Structure.- 3. Enzyme-Inhibitor Interactions.- 3.1. Overview.- 3.2. DHFR-Methotrexate Complexes.- 3.3. DHFR-Trimethoprim Complexes.- 4. Examples of Inhibitor Design.- 4.1. Trimethoprim Analogs with Acidic Substituents.- 4.2. Conformationally Restricted Analogs of Trimethoprim.- 5. Conclusion.- References.- VII. Macromolecules and Targeted Drug Delivery.- 16 Control of the Biological Dispersion of Therapeutic Proteins.- 1. Introduction.- 2. Therapeutic Proteins.- 2.1. Type.- 2.2. Physical and Chemical Properties.- 3. Clinical Use.- 3.1. Site and Mode of Action.- 3.2. Endocrine-Like and Para-/Autocrine-Like Mediators.- 4. Protectants.- 5. Protein (Re)glycosylation.- 5.1. Oligosaccharide Variability and Recognition.- 5.2. Biotechnological Processes.- 5.3. Protein Remodeling.- 5.4. Enzyme-Storage Diseases.- 5.5. Deglycosylation.- 6. Protein Hybrids.- 6.1. Cell Processing.- 6.2. Gene-Fusion Hybrids.- 6.3. Synthetically Linked Hybrid Conjugates.- 6.4. Antibodies.- 7. Administration.- 7.1. Route, Rate, and Frequency of Input.- 7.2. Parenteral/Interstitial Administration.- 7.3. Gastrointestinal Tract.- 7.4. Nasal and Buccal Mucosae.- 8. Concluding Remarks.- References.- 17 Antibody-Mediated Drug Delivery.- 1. Introduction.- 2. Global and Regional Pharmacokinetics.- 3. Microvascular Transport.- 4. Tissue Level: The Percolation Problem.- 5. Percolation Calculations and the Binding Site Barrier.- 6. Concluding Remarks.- References.- 18 Semisynthetic Catalytic Antibodies.- 1. Design Considerations.- 2. Synthesis of Affinity Labels.- 3. Antibody Modification.- 3.1. Affinity Labeling.- 3.2. Cleavage of Labels and Isolation of Stable S-Thiopyridyl Adducts.- 4. Determination of Modified Site.- 5. Ester Cleavage Using Thiol-Derivatized Antibody.- 5.1. Synthesis of Substrates.- 5.2. Ester Cleavage Assays.- 5.3. Substrate Specificity and Enantioselectivity.- 6. Derivatization with Imidazole.- 7. Derivatization with a Spectroscopic Probe.- 8. Prospects.- References.- VIII. Strategies for Directed Mutagenesis of Proteins.- 19 Engineering Novel, Prolonged-Acting Insulins.- 1. Introduction.- 1.1. Background and Aims.- 1.2. Rationale of Design and Mode of Action of Prolonged-Acting, Soluble Insulins.- 2. Synthesis of Insulin Analogs.- 2.1. The Tryptic Transpeptidation Reaction.- 2.2. Single-Chain Des-(B30) Insulins.- 2.3. Biosynthesis in Yeast.- 2.4. Substitutions that Increase pI.- 2.5. Substitutions that Stabilize Insulin.- 3. Biological Evaluation.- 3.1. Free Fat Cell Bioassay.- 3.2. Mouse Blood Glucose Assay.- 3.3. Index of Prolongation.- 3.4. Absorption Kinetics in Pigs Using External ?-Counting.- 4. Crystallization Techniques.- 4.1. Micro Reaction Chamber.- 4.2. Hanging-Drop Crystallization.- 4.3. Crystallization In Vivo.- 5. Results and Discussion.- 5.1. Substitutions that Enhance the Prolonged Action.- 5.2. Substitutions without Significant Effect on Absorption.- 5.3. Substitutions that Enhance Stability.- 5.4. Failure of Expression of ProA21.- 5.5. Galenic Factors Influencing Absorption Kinetics.- 6. Preclinical Studies and Considerations.- 6.1. Reproducibility of Absorption.- 6.2. Calculation of Variations in Depots and Blood Levels of Basal Insulin in the Steady State.- 6.3. Potency and Units.- 6.4. Immunogenicity.- 7. Summary.- References.- IX. Design of Novel Antiviral Agents and Vaccines.- 20 Studies on the Structure and Function of Ubiquitin.- 1. Introduction.- 2. Synthesis and Expression of Ubiquitin and Mutant Genes in Yeast and Escherichia coli.- 3. Disulfide Mutants.- 4. Carboxy Terminal Peptides.- 5. Conclusions.- References.- 21 Recognition at Membrane Surfaces: Influenza HA and Human HLA.- 1. Introduction.- 2. HA-Cell Receptor Interaction.- 2.1. Nuclear Magnetic Resonance and Solution Studies of Binding.- 2.2. Antigenic Variation and Inhibitor Design.- 3. Virus Entry and Membrane Fusion.- 4. Human Histocompatibility Antigens.- 4.1. The Structure of HLA-A2.- 4.2. Peptide Binding.- 4.3. The Structure of HLA-A28.- 4.4. Modeling Class II Histocompatibility Antigens.- References.
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