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1 Soluble Synthetic Combinatorial Libraries: The Use of Molecular Diversities for Drug Discovery

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Combinatorial Libraries
This chapter is in the book Combinatorial Libraries
A Synthetic Peptide Libraries 1 Soluble Synthetic Combinatorial Libraries: The Use of Molecular Diversities for Drug Discovery Barbara Dörner, Sylvie E. Blondelle, Clemencia Pinilla, Jon Appel, Colette T. Dooley, Jutta Eichler, John M. Ostresh, Enrique Pérez-Payá and Richard A. Houghten 1.1 Introduction Methods for the generation and systematic screening of immense molecular diversities (i.e., tens to hundreds of millions of compounds) have recently been developed and represent a powerful tool in the search for novel pharmacological agents [reviewed in (Gallop et al., 1994; Gordon et al., 1994; Blondelle et al., 1995a; Pinilla et al., 1995)]. A number of different strategies based on the princi-ple of solid phase synthesis are now available to prepare these diversities in a manner which permits their ready use in biological screening. The synthesis of libraries was originally focused on peptides and nucleotides, for which synthetic procedures were straightforward and well established. Peptides are key media-tors of biochemical information and have long been used as starting compounds for the development of novel drugs, even though they have limitations as poten-tial therapeutic agents due to their typical lack of oral activity, susceptibility to proteolytic breakdown, and inability to pass through the blood brain barrier. Due to these limitations, recent trends in this field have been directed toward the preparation of chemical libraries as potential sources for improved leads for drug discovery. Powerful chemical methods have been developed which take advan-tage of solid phase synthetic procedures for the generation of a wide range of compounds having novel physiological properties. Thus, a variety of novel solid phase-based chemistries enable the generation of libraries of organic molecules in an efficient and reproducible manner.

A Synthetic Peptide Libraries 1 Soluble Synthetic Combinatorial Libraries: The Use of Molecular Diversities for Drug Discovery Barbara Dörner, Sylvie E. Blondelle, Clemencia Pinilla, Jon Appel, Colette T. Dooley, Jutta Eichler, John M. Ostresh, Enrique Pérez-Payá and Richard A. Houghten 1.1 Introduction Methods for the generation and systematic screening of immense molecular diversities (i.e., tens to hundreds of millions of compounds) have recently been developed and represent a powerful tool in the search for novel pharmacological agents [reviewed in (Gallop et al., 1994; Gordon et al., 1994; Blondelle et al., 1995a; Pinilla et al., 1995)]. A number of different strategies based on the princi-ple of solid phase synthesis are now available to prepare these diversities in a manner which permits their ready use in biological screening. The synthesis of libraries was originally focused on peptides and nucleotides, for which synthetic procedures were straightforward and well established. Peptides are key media-tors of biochemical information and have long been used as starting compounds for the development of novel drugs, even though they have limitations as poten-tial therapeutic agents due to their typical lack of oral activity, susceptibility to proteolytic breakdown, and inability to pass through the blood brain barrier. Due to these limitations, recent trends in this field have been directed toward the preparation of chemical libraries as potential sources for improved leads for drug discovery. Powerful chemical methods have been developed which take advan-tage of solid phase synthetic procedures for the generation of a wide range of compounds having novel physiological properties. Thus, a variety of novel solid phase-based chemistries enable the generation of libraries of organic molecules in an efficient and reproducible manner.

Chapters in this book

  1. Frontmatter I
  2. Introduction V
  3. Contents VII
  4. A Synthetic Peptide Libraries
  5. 1 Soluble Synthetic Combinatorial Libraries: The Use of Molecular Diversities for Drug Discovery 1
  6. 2 Combinatorial Libraries of Synthetic Structures: Synthesis, Screening, and Structure Determination 27
  7. 3 Peptide Libraries Bound to Continuous Cellulose Membranes: Tools to Study Molecular Recognition 53
  8. Β Nucleic Acids Libraries
  9. 4 In Vitro Selection of Nucleic Acid Sequences that Bind Small Molecules 69
  10. 5 Discovery and Characterization of a Thrombin Aptamer Selected from a Combinatorial ssDNA Library 87
  11. C Phage Display of Peptide Libraries
  12. 6 Structural and Functional Constraints in the Display of Peptides on Filamentous Phage Capsids 113
  13. 7 Conformationally Defined Peptide Libraries on Phage: Selectable Templates for the Design of Pharmacological Agents 127
  14. 8 Discovery of Disease-Specific Mimotopes by Screening Phage Libraries with Human Serum Samples 145
  15. 9 The Utilization of Platelets and Whole Cells for the Selection of Peptides Ligands from Phage Display Libraries 159
  16. 10 Identification of MHC Binding Motifs with Synthetic and Phage Displayed Peptide Libraries 175
  17. D Phage Display of Protein Domains
  18. 11 Isolating High Affinity Human Antibodies from Phage Repertoires 189
  19. 12 Altering the Function of Enzymes and Macromolecular Inhibitors by Phage Display 205
  20. Authors 223
  21. Index 227
  22. Backmatter 233
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https://doi.org/10.1515/9783110808902.1

Chapters in this book

  1. Frontmatter I
  2. Introduction V
  3. Contents VII
  4. A Synthetic Peptide Libraries
  5. 1 Soluble Synthetic Combinatorial Libraries: The Use of Molecular Diversities for Drug Discovery 1
  6. 2 Combinatorial Libraries of Synthetic Structures: Synthesis, Screening, and Structure Determination 27
  7. 3 Peptide Libraries Bound to Continuous Cellulose Membranes: Tools to Study Molecular Recognition 53
  8. Β Nucleic Acids Libraries
  9. 4 In Vitro Selection of Nucleic Acid Sequences that Bind Small Molecules 69
  10. 5 Discovery and Characterization of a Thrombin Aptamer Selected from a Combinatorial ssDNA Library 87
  11. C Phage Display of Peptide Libraries
  12. 6 Structural and Functional Constraints in the Display of Peptides on Filamentous Phage Capsids 113
  13. 7 Conformationally Defined Peptide Libraries on Phage: Selectable Templates for the Design of Pharmacological Agents 127
  14. 8 Discovery of Disease-Specific Mimotopes by Screening Phage Libraries with Human Serum Samples 145
  15. 9 The Utilization of Platelets and Whole Cells for the Selection of Peptides Ligands from Phage Display Libraries 159
  16. 10 Identification of MHC Binding Motifs with Synthetic and Phage Displayed Peptide Libraries 175
  17. D Phage Display of Protein Domains
  18. 11 Isolating High Affinity Human Antibodies from Phage Repertoires 189
  19. 12 Altering the Function of Enzymes and Macromolecular Inhibitors by Phage Display 205
  20. Authors 223
  21. Index 227
  22. Backmatter 233
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