Chapter Four

Application of Recombinant DNA Technology in Medicinal Chemistry and Drug Discovery soumitra basu University of Pittsburgh Center for Pharmacogenetics Department of Pharmaceutical Sciences Pittsburgh, Pennsylvania

Adegboyega K. Oyelere Rib-X Pharmaceuticals, Inc. N^f Haven, Connecticut

Burger's Medicinal Chemistry and Drug Discovery Sixth Edition, Volume 2: Drug Development Edited by Donald J. Abraham ISBN 0-471-37028-2 © 2003John Wiley & Sons, Inc.

Contents

1 Introduction, 82

1.1 Chemistry-Driven Drug Discovery, 82

1.2 Advent of Recombinant DNA Technology, 83

2 New Therapeutics from Recombinant DNA Technology, 83

3 Protein Engineering and Site-Directed Mutagenesis, 84

3.1 Second-Generation Protein Therapeutics, 84

3.2 Antibody-Based Therapeutics, 88

3.3 Epitope Mapping, 88

3.4 Future Directions, 89

4 Genetically Engineered Drug Discovery Tools, 91

4.1 Reagents for Screening, 91

4.2 Combinatorial Biosynthesis and Microbe ReEngineering, 92

4.3 SELEX or In Vitro Evolution, 92

4.3.1 Aptamers as Drugs, 93

4.3.2 Aptamers as Diagnostics, 94

4.4 Phage Display, 94

4.4.1 Preparation of Phage Display Libraries, 94

4.4.2 Phage Display Selections against Purified Proteins, 95

4.4.3 Cell-Specific Targeting, 95

4.4.4 In Vivo Phage Display, 96

4.5 Reagents for Structural Biology Studies, 96

4.6 Enzymes as Drug Targets, 96

4.7 Receptors as Drug Targets, 100

4.8 Cellular Adhesion Proteins, 105

5 Future Prospects, 106

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