Protein and Peptide Mass Spectrometry in Drug Discovery

Overview

With chapters provided by international leading experts, this book covers the most recent advancements in this area. Focusing on the pharmaceutical industry, the book addresses both emerging mass spectrometry techniques, including imaging mass spectrometry, ion mobility, and microwave-assisted mass spectrometry, and recent applications, including pharmaceutical analysis throughout each stage of drug development. The book stresses practice and applications, providing real world examples from industry contributors....

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Overview

With chapters provided by international leading experts, this book covers the most recent advancements in this area. Focusing on the pharmaceutical industry, the book addresses both emerging mass spectrometry techniques, including imaging mass spectrometry, ion mobility, and microwave-assisted mass spectrometry, and recent applications, including pharmaceutical analysis throughout each stage of drug development. The book stresses practice and applications, providing real world examples from industry contributors. The book starts with an overview of protein mass spectrometry (MS) methodology, followed by a discussion of studies involving the characterization of proteins and special topics related to drug discovery. Remaining chapters address newer techniques for determining protein structure, interactions with peptides, proteins, and ligands, and protein folding and unfolding.

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Editorial Reviews

From the Publisher
"This book will be a valuable reference as it contains plenty of depth and substance to be of interest to experienced practitioners of mass spectrometry and related techniques, but is still accessible to pharmaceutical researchers who want to learn more about MS technologies and its applications."  (American Society for Mass Spectrometry, 1 July 2012)
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Product Details

  • ISBN-13: 9780470258170
  • Publisher: Wiley
  • Publication date: 11/8/2011
  • Edition number: 1
  • Pages: 492
  • Product dimensions: 6.20 (w) x 9.40 (h) x 1.20 (d)

Meet the Author

Michael L. Gross, PhD, is a Professor in the Departments of Chemistry, Medicine, and Immunology at Washington University in St. Louis. He is also Principal Investigator at the National Institutes of Health (NIH) Research Resource in Mass Spectrometry.

Guodong Chen, PhD, is Principal Scientist in Bioanalytical and Discovery Analytical Sciences at Bristol-Myers Squibb in Princeton, New Jersey. He heads a mass spectrometry group in support of drug discovery as well as development programs in small molecule pharmaceuticals and biologics.

Birendra N. Pramanik, PhD, was a Distinguished Fellow at Schering-Plough Research Institute (SPRI), where he directed the spectroscopy, mass spectrometry, and NMR programs.

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Table of Contents

PREFACE xv

CONTRIBUTORS xvii

PART I METHODOLOGY 1

1 Ionization Methods in Protein Mass Spectrometry 3
Ismael Cotte-Rodriguez, Yun Zhang, Zhixin Miao, and Hao Chen

1.1 History of the Development of Protein Mass Spectrometry 4

1.2 Laser-Based Ionization Methods for Proteins 5

1.3 Spray-Based Ionization Methods for Proteins 13

1.4 Ambient Ionization Methods 20

1.5 Conclusions 30

Acknowledgments 30

References 30

2 Ion Activation and Mass Analysis in Protein Mass Spectrometry 43
Cheng Lin and Peter O’Connor

2.1 Introduction 43

2.2 Ion Activation and Tandem MS Analysis 46

2.3 Mass Analyzers 59

References 81

3 Target Proteins: Bottom-up and Top-down Proteomics 89
Michael Boyne and Ron Bose

3.1 Mass Spectral Approaches to Targeted Protein Identification 89

3.2 Bottom-up Proteomics 90

3.3 Top-down Approaches 96

3.4 Next-Generation Approaches 98

References 99

4 Quantitative Proteomics by Mass Spectrometry 101
Jacob Galan, Anton Iliuk, and W. Andy Tao

4.1 Introduction 101

4.2 In-Cell Labeling 105

4.3 Quantitation via Isotopic Labeling of Proteins 107

4.4 Quantitation via Isotopic Labeling on Peptides 112

4.5 Label-Free Quantitation 116

4.6 Conclusions 119

Acknowledgment 120

References 120

5 Comparative Proteomics by Direct Tissue Analysis Using Imaging Mass Spectrometry 129
Michelle L. Reyzer and Richard M. Caprioli

5.1 Introduction 129

5.2 Conventional Comparative Proteomics 130

5.3 Comparative Proteomics Using Imaging MS 131

5.4 Conclusions 136

Acknowledgments 137

References 137

6 Peptide and Protein Analysis Using Ion Mobility–Mass Spectrometry 139
Jeffrey R. Enders, Michal Kliman, Sevugarajan Sundarapandian, and John A. McLean

6.1 Ion Mobility–Mass Spectrometry: Instrumentation and Separation Selectivity 139

6.2 Characterizing and Interpreting Peptide and Protein Structures 147

6.3 Applications of IM-MS to Peptide and Protein Characterizations 152

6.4 Future Directions 158

Acknowledgments 159

References 160

7 Chemical Footprinting for Determining Protein Properties and Interactions 175
Sandra A. Kerfoot and Michael L. Gross

7.1 Introduction to Hydrogen–Deuterium Exchange 175

7.2 Experimental Procedures 178

7.3 Mass Spectrometry-Based HDX in Practice 182

7.4 Protein Footprinting via Free-Radical Oxidation 193

7.5 Chemical Crosslinking 198

7.6 Selective and Irreversible Chemical Modification 201

7.7 Conclusion 205

References 206

8 Microwave Technology to Accelerate Protein Analysis 213
Urooj A. Mirza, Birendra N. Pramanik, and Ajay K. Bose

8.1 Introduction 213

8.2 Microwave Technology 215

8.3 Summary 224

Acknowledgments 224

References 224

9 Bioinformatics and Database Searching 231
Surendra Dasari and David L. Tabb

9.1 Overview 231

9.2 Introduction to Tandem Mass Spectrometry 231

9.3 Overview of Peptide Identification with Database Searching 234

9.4 MyriMatch-IDPicker Protein Identification Pipeline 235

9.5 Results of a Shotgun Proteomics Study 246

9.6 Improvements to MyriMatch Database Search Engine 248

9.7 Applications of MyriMatch-IDPicker Pipeline 250

9.8 Conclusions 251

Acknowledgments 251

References 251

PART II Applications 253

10 Mass Spectrometry-Based Screening and Characterization of Protein–Ligand Complexes in Drug Discovery 255
Christine L. Andrews, Michael R. Ziebell, Elliott Nickbarg, and Xianshu Yang

10.1 Introduction 255

10.2 Affinity Selection Mass Spectrometry (AS-MS) 256

10.3 Solution-Based AS-MS as Screening Technologies 258

10.4 Gas-Phase Interactions 267

10.5 Enzyme Activity Assays Using MS for Screening or Confirming Drug Candidates 271

10.6 Conclusions and Future Directions 276

References 277

11 Utilization of Mass Spectrometry for the Structural Characterization of Biopharmaceutical Protein Products 287
Amareth Lim and Catherine A. Srebalus Barnes

11.1 Introduction 287

11.2 MS-Based Approach for the Characterization of Recombinant Therapeutic Proteins 288

11.3 Cell Culture Development 290

11.4 Purification Development 294

11.5 Formulation Development 300

11.6 Analytical Method Development 304

11.7 Confirmation of Structure/Product Comparability Assessment 311

11.8 Conclusions 313

Acknowledgments 315

References 315

12 Post-translationally Modified Proteins: Glycosylation, Phosphorylation, and Disulfide Bond Formation 321
Anthony Tsarbopoulos and Fotini N. Bazoti

12.1 Introduction 321

12.2 Glycosylation 322

12.3 Phosphorylation 338

12.4 Disulfide Bond Detection and Mapping 347

12.5 Future Perspectives 350

Acknowledgments 352

Abbreviations 353

References 354

13 Mass Spectrometry of Antigenic Peptides 371
Henry Rohrs

13.1 Introduction 371

13.2 Analysis of Antigenic Peptides 374

13.3 Examples of the Application of Mass Spectrometry to Antigenic Peptide Study 381

13.4 Future Work 385

Acknowledgments 386

Abbreviations 387

References 387

14 Neuropeptidomics 393
Jonathan V. Sweedler, Fang Xie, and Adriana Bora

14.1 Introduction 393

14.2 Neuropeptidomics: Characterizing Peptides in the Brain 394

14.3 Sample Preparation for Mass Spectrometry 395

14.4 Separations 405

14.5 Peptide Characterization via Mass Spectrometry 407

14.6 Conclusions 419

14.7 Future Perspectives 419

Acknowledgments 420

References 420

15 Mass Spectrometry for the Study of Peptide Drug Metabolism 435
Patrick J. Rudewicz

15.1 Introduction 435

15.2 Peptide Drug Metabolism 436

15.3 LC-MS/MS for Metabolite Identification 437

15.4 Quantitative Analysis 439

15.5 Case Study: IL-1b Protease Inhibitors 440

15.6 Future Directions 445

References 445

INDEX 449

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