EnzymE TEchnologiEs chEmicAl Biology oF EnzymEs FoR BioTEchnology AnD PhARmAcEUTicAl APPlicATions (A Series Consisting of Three Volumes) Volume I. Enzyme Technologies: Metagenomics, Evolution, Biocatalysis, and Biosynthesis Editors: Wu-Kuang Yeh, Hsiu-Chiung Yang, and James R. McCarthy Volume II. Enzyme Technologies: Pluripotent Players in Discovering Therapeutic Agents Editors: Hsiu-Chiung Yang, Wu-Kuang Yeh, and James R. McCarthy Volume III. Enzyme Technologies: Two Facets of Modern Structure-Based Design Editors: James R. McCarthy, Hsiu-Chiung Yang, and Wu-Kuang Yeh EnzymE TEchnologiEs Pluripotent Players in Discovering Therapeutic Agents Edited by hsiU-chiUng yAng Eli Lilly and Company Indianapolis, Indiana WU-KUAng yEh Indiana University Purdue University Indianapolis Indianapolis, Indiana JAmEs R. mccARThy Indiana University Purdue University Indianapolis Indianapolis, Indiana Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved. 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QP601.5.M33 2014 615.3–dc23 2013013968 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 conTEnTs conTRiBUToRs vii PREFAcE ix PART A EnzymEs – EssEnTiAl WoRKhoRsEs in PhARmAcEUTicAl REsEARch 1 1 Assay Technologies for Proteases 3 Anuradha Roy, Gerald H. Lushington, James McGee, and Rathnam Chaguturu 2 Discovery and Development of isozyme-selective inhibitors involved in lipid metabolism 55 Taichi Ohshiro and Hiroshi Tomoda 3 covalent Enzyme inhibition in Drug Discovery and Development 81 Shujaath Mehdi 4 Preclinomics: Enzyme Assays and Rodent models for metabolic diseases 131 Wu-Kuang Yeh and Richard G. Peterson PART B EnzymEs – inDisPEnsABlE Tools FoR imPRoving DRUggABiliTy 163 5 Enzymes and Targeted Activation of Prodrugs 165 Yanhui Yang, Yu Chen, Herve Aloysius, Daigo Inoyama, and Longqin Hu v vi CoNTENTS 6 Evolution of an orally Active Prodrug of gemcitabine 237 James R. McCarthy 7 Enzymatically Activated Phosphate and Phosphonate Prodrugs 253 Ivan S. Krylov and Charles E. McKenna PART c EnzymEs – PoWERFUl WEAPons FoR coRREcTing nATURE’s ERRoRs 301 8 Treatment options for mucopolysaccharidosis Type ii (hunter’s syndrome) 303 Michael Beck 9 Enzyme Replacement Therapy for Fabry Disease 321 Ley Nadine Lacbawan, Wei Zheng, and Ozlem Goker-Alpan 10 methods and Principles of Pancreatic Function Tests 335 Henrike von Schassen, Jutta Keller, and Peter Layer index 341 conTRiBUToRs herve Aloysius, ms, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey michael Beck, mD, University Medical Center, Children’s Hospital, Mainz, Germany Rathnam chaguturu, PhD, Del Shankel Structural Biology Center, High Throughput Screening Laboratory, Lawrence, Kansas; SRI International, Harrisonburg, Virginia yu chen, ms, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey ozlem goker-Alpan, PhD, LSD Research and Treatment Unit, Center for Clinical Trials, Fairfax, Virginia longqin hu, PhD, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey Daigo inoyama, Bs, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey Jutta Keller, mD, Department of Internal Medicine, Israelitic Hospital in Hamburg, Hamburg, Germany ivan s. Krylov, PhD, Department of Chemistry, University of Southern California, Los Angeles, California ley nadine lacbawan, PhD, LSD Research and Treatment Unit, Center for Clinical Trials, Fairfax, Virginia vii viii CoNTRIBUToRS Peter layer, mD, PhD, FAcg, AgAF, Department of Internal Medicine, Israelitic Hospital in Hamburg, Hamburg, Germany gerald h. lushington, PhD, Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas; LiS Consulting, Lawrence, Kansas James R. mccarthy, PhD, Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana James mcgee, PhD, Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana charles E. mcKenna, PhD, Department of Chemistry, University of Southern California, Los Angeles, California shujaath mehdi, PhD, Immunoinflammation Therapeutic Strategy Unit, Sanofi Pharmaceuticals, Bridgewater, New Jersey Taichi ohshiro, PhD, Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan; Section on Lipid Sciences, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Richard g. Peterson, PhD, PreClinomics, Inc., Indianapolis, Indiana Anuradha Roy, PhD, Del Shankel Structural Biology Center, High Throughput Screening Laboratory, Lawrence, Kansas henrike von schassen, mD, Department of Internal Medicine, Israelitic Hospital in Hamburg, Hamburg, Germany hiroshi Tomoda, PhD, Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan yanhui yang, PhD, Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey Wu-Kuang yeh, PhD, Indiana University Purdue University Indianapolis, Indianapolis, Indiana Wei zheng, PhD, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland