Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`Norbert Sewald and Hans-Dieter Jakubke
`Peptides: Chemistry and Biology
`
`MPI EXHIBIT 1067 PAGE 1
`
`MPI EXHIBIT 1067 PAGE 1
`
`

`

`Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`Norbert Sewald and Hans-Dieter Jakubke
`
`Peptides: Chemistry and Biology
`
`MPI EXHIBIT 1067 PAGE 2
`
`MPI EXHIBIT 1067 PAGE 2
`
`

`

`Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`Prof. Dr. Norbert Sewald
`Universität Bielefeld
`Fakultät für Chemie
`Organ. und Bioorgan. Chemie
`PO Box 100131
`33501 Bielefeld, Germany
`
`Prof. em. Dr. Hans-Dieter Jakubke
`Universität Leipzig
`Institut für Biochemie
`Private address:
`Albert-Richter-Straße 12
`01465 Dresden-Langebrück, Germany
`
`Cover
`The cover picture shows the TPR1 domain of Hop
`in complex with -Gly-Pro-Thr-Ile-Glu-Glu-Val-
`Asp-OH (GPTIEEVD). TPR domains participate in
`the ordered assembly of Hsp70-Hsp90 multichape-
`rone complexes.
`The TPR1 domain of the adaptor protein Hop
`specifically recognizes the C-terminal heptapep-
`tide -Pro-Thr-Ile-Glu-Glu-Val-Asp-OH (PTIEEVD)
`of the chaperone Hsp70 while the TPR2A domain
`of Hop binds the C-terminal pentapeptide -Met-
`Glu-Glu-Val-Asp-OH (MEEVD) of the chaperone
`Hsp90. The EEVD motif is conserved in all solu-
`ble forms of eukaryotic Hsp70 and Hsp90 pro-
`teins.
`Peptide binding is mediated with the EEVD motif.
`Both carboxy groups of the C-terminal aspartate
`anchor the peptide by electrostatic interactions.
`The hydrophobic residues located N-terminally
`within the peptide are critical for specificity.
`[C. Scheufler, A. Brinker, G. Bourenkov, S. Pegora-
`ro, L. Moroder, H. Bartunik, F. U. Hartl, I. Moarefi,
`Structure of TPR domain-peptide complexes: criti-
`cal elements in the assembly of the Hsp70-Hsp90
`multichaperone machine, Cell 2000, 101, 199; PDB
`entry 1ELW (http://www.rcsb.org/pdb/)]
`
`n This book was carefully produced. Nevertheless,
`authors and publisher do not warrant the infor-
`mation contained therein to be free of errors.
`Readers are advised to keep in mind that state-
`ments, data, illustrations, procedural details or
`other items may inadvertently be inaccurate.
`
`The use of general descriptive names, registered
`names, trademarks, etc. in this book does not im-
`ply, even in the absence of a specific statement,
`that such names are exempt from the relevant
`protective laws and regulations and therefore free
`for general use.
`
`Library of Congress Card No.: applied for
`
`British Library Cataloguing-in-Publication Data
`A catalogue record for this book is available from
`the British Library.
`
`Die Deutsche Bibliothek – CIP-Cataloguing-in-
`Publication Data
`A catalogue record for this publication is available
`from Die Deutsche Bibliothek.
`
`© WILEY-VCH Verlag GmbH
`D-69469 Weinheim, 2002
`
`All rights reserved (including those of translation
`in other languages). No part of this book may be
`reproduced in any form – by photoprinting, mi-
`crofilm, or any other means – nor transmitted or
`translated into machine language without written
`permission from the publishers. Registered
`names, trademarks, etc. used in this book, even
`when not specifically marked as such, are not to
`be considered unprotected by law.
`
`Printed in the Federal Republic of Germany
`Printed on acid-free paper
`
`Typesetting K+V Fotosatz GmbH, Beerfelden
`Printing betz-druck gmbH, Darmstadt
`Bookbinding
`J. Schäffer GmbH & Co.KG,
`Grünstadt
`
`ISBN 3-527-30405-3
`
`MPI EXHIBIT 1067 PAGE 3
`
`MPI EXHIBIT 1067 PAGE 3
`
`

`

`Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`V
`
`Contents
`
`Preface XI
`
`Abbreviations XIII
`
`1
`
`Introduction and Background 1
`
`2
`2.1
`2.2
`2.3
`2.3.1
`2.3.1.1
`2.3.1.2
`2.3.1.3
`2.3.1.4
`2.3.2
`2.3.2.1
`2.3.2.2
`2.3.2.3
`2.3.2.4
`2.3.2.5
`2.3.2.6
`2.3.2.7
`2.3.2.8
`2.3.2.9
`2.3.2.10
`2.4
`2.4.1
`2.4.1.1
`2.4.1.2
`2.4.1.3
`2.4.1.4
`2.4.2
`2.4.2.1
`
`Fundamental Chemical and Structural Principles
`5
`Definitions and Main Conformational Features of the Peptide Bond 5
`Building Blocks, Classification, and Nomenclature
`7
`Analysis of the Covalent Structure of Peptides and Proteins 11
`Separation and Purification 12
`Separation Principles
`12
`Purification Techniques 16
`Stability Problems 18
`Evaluation of Homogeneity 19
`Primary Structure Determination 20
`End Group Analysis
`21
`Cleavage of Disulfide Bonds 23
`Analysis of Amino Acid Composition 24
`Selective Methods of Cleaving Peptide Bonds 25
`N-Terminal Sequence Analysis (Edman Degradation)
`C-terminal Sequence Analysis
`29
`Mass Spectrometry 30
`Peptide Ladder Sequencing 32
`Assignment of Disulfide Bonds and Peptide Fragment Ordering 33
`Location of Post-Translational Modifications and Bound Cofactors 35
`Three-Dimensional Structure
`36
`Secondary Structure 36
`Helix 37
`b-Sheet
`38
`Turns 39
`Amphiphilic Structures
`Tertiary Structure
`43
`Structure Prediction 46
`
`27
`
`41
`
`MPI EXHIBIT 1067 PAGE 4
`
`MPI EXHIBIT 1067 PAGE 4
`
`

`

`VI
`
`Contents
`
`2.5
`2.5.1
`2.5.2
`2.5.3
`2.5.4
`2.5.5
`2.6
`
`3
`3.1
`3.2
`3.2.1
`3.2.2
`3.2.2.1
`3.2.2.2
`3.2.2.3
`3.2.2.4
`3.2.2.5
`3.2.2.6
`3.2.2.7
`3.2.2.8
`3.2.2.9
`3.2.3
`3.3
`3.3.1
`3.3.1.1
`3.3.1.2
`3.3.1.3
`3.3.1.4
`3.3.1.5
`3.3.1.6
`3.3.2
`3.3.2.1
`3.3.2.2
`3.3.2.3
`3.3.3
`3.3.3.1
`3.3.3.2
`3.3.4
`3.4
`
`4
`4.1
`4.1.1
`4.1.1.1
`
`47
`
`Methods of Structural Analysis
`Circular Dichroism 48
`Infrared Spectroscopy 49
`NMR Spectroscopy 50
`X-Ray Crystallography
`52
`UV Fluorescence Spectroscopy 54
`References 55
`
`Biologically Active Peptides
`61
`Occurrence and Biological Roles 61
`Biosynthesis 73
`Ribosomal Synthesis
`73
`Post-translational Modification 76
`Enzymatic Cleavage of Peptide Bonds 76
`Hydroxylation 78
`Carboxylation 78
`Glycosylation 78
`Amidation 83
`Phosphorylation 83
`Lipidation 85
`Pyroglutamyl Formation 86
`Sulfatation 87
`Nonribosomal Synthesis
`88
`Selected Bioactive Peptide Families 90
`Peptide and Protein Hormones 90
`Liberins and Statins
`92
`Pituitary Hormones 96
`Neurohypophyseal Hormones 98
`Gastrointestinal Hormones 99
`Pancreatic Islet Hormones 100
`Further Physiologically Relevant Peptide Hormones 103
`Neuropeptides 107
`Opioid Peptides 109
`Tachykinins
`114
`Further Selected Neuroactive Peptides 116
`Peptide Antibiotics 119
`Nonribosomally Synthesized Peptide Antibiotics 119
`Ribosomally Synthesized Peptide Antibiotics 124
`Peptide Toxins 126
`References 130
`
`Peptide Synthesis
`135
`Principles and Objectives 135
`Main Targets of Peptide Synthesis
`135
`Confirmation of Suggested Primary Structures 135
`
`MPI EXHIBIT 1067 PAGE 5
`
`MPI EXHIBIT 1067 PAGE 5
`
`

`

`Design of Bioactive Peptide Drugs
`136
`Preparation of Pharmacologically Active Peptides and Proteins 137
`Synthesis of Model Peptides 138
`Basic Principles of Peptide Bond Formation 139
`Protection of Functional Groups 142
`Na-Amino Protection 143
`Alkoxycarbonyl-Type (Urethane-Type) Protecting Groups 143
`Carboxamide-Type Protecting Groups 152
`Sulfonamide and Sulfenamide-Type Protecting Groups 152
`Alkyl-Type Protecting Groups 153
`Ca-Carboxy Protection 154
`Esters 155
`Amides and Hydrazides 157
`C-terminal and Backbone Na-Carboxamide Protection 160
`Side-chain Protection 162
`Guanidino Protection 162
`x-Amino Protection 165
`x-Carboxy Protection 166
`Thiol Protection 168
`Imidazole Protection 171
`Hydroxy Protection 174
`Thioether Protection 176
`Indole Protection 177
`x-Amide Protection 178
`Enzyme-labile Protecting Groups 180
`Enzyme-labile Na-Amino Protection 181
`Enzyme-labile Ca-Carboxy Protection and Enzyme-labile Linker
`Moieties 182
`Protecting Group Compatibility
`Peptide Bond Formation 184
`Acyl Azides 185
`Anhydrides
`186
`Mixed Anhydrides
`187
`Symmetrical Anhydrides
`N-Carboxy Anhydrides
`Carbodiimides 191
`Active Esters 195
`Acyl Halides 200
`Phosphonium Reagents
`Uronium Reagents 202
`Further Special Methods 204
`Racemization During Synthesis
`Direct Enolization 205
`5(4H)-Oxazolone Mechanism 205
`Racemization Tests: Stereochemical Product Analysis
`
`189
`190
`
`Contents VII
`
`208
`
`184
`
`201
`
`205
`
`4.1.1.2
`4.1.1.3
`4.1.1.4
`4.1.2
`4.2
`4.2.1
`4.2.1.1
`4.2.1.2
`4.2.1.3
`4.2.1.4
`4.2.2
`4.2.2.1
`4.2.2.2
`4.2.3
`4.2.4
`4.2.4.1
`4.2.4.2
`4.2.4.3
`4.2.4.4
`4.2.4.5
`4.2.4.6
`4.2.4.7
`4.2.4.8
`4.2.4.9
`4.2.5
`4.2.5.1
`4.2.5.2
`
`4.2.6
`4.3
`4.3.1
`4.3.2
`4.3.2.1
`4.3.2.2
`4.3.2.3
`4.3.3
`4.3.4
`4.3.5
`4.3.6
`4.3.7
`4.3.8
`4.4
`4.4.1
`4.4.2
`4.4.3
`
`MPI EXHIBIT 1067 PAGE 6
`
`MPI EXHIBIT 1067 PAGE 6
`
`

`

`VIII
`
`Contents
`
`209
`212
`
`Solid-Phase Peptide Synthesis (SPPS)
`4.5
`Solid Supports and Linker Systems
`4.5.1
`Safety-Catch Linkers 220
`4.5.2
`Protection Schemes 224
`4.5.3
`Boc/Bzl-protecting Groups Scheme (Merrifield Tactics)
`4.5.3.1
`224
`Fmoc/tBu-protecting Groups Scheme (Sheppard Tactics) 225
`4.5.3.2
`Three- and More-Dimensional Orthogonality
`4.5.3.3
`227
`Chain Elongation 227
`4.5.4
`Coupling Methods 227
`4.5.4.1
`Undesired Problems During Elongation 228
`4.5.4.2
`Difficult Sequences 230
`4.5.4.3
`On-Resin Monitoring 232
`4.5.4.4
`Automation of the Process 232
`4.5.5
`Special Methods 233
`4.5.6
`Peptide Cleavage from the Resin 235
`4.5.7
`Acidolytic Methods 235
`4.5.7.1
`Side reactions 236
`4.5.7.2
`Advantages and Disadvantages of the Boc/Bzl and Fmoc/tBu
`4.5.7.3
`Schemes 237
`4.5.8
`Examples of Syntheses by Linear SPPS 237
`4.6
`Biochemical Synthesis
`238
`4.6.1
`Recombinant DNA Techniques 239
`4.6.1.1
`Principles of DNA Technology
`239
`4.6.1.2
`Examples of Synthesis by Genetic Engineering 243
`4.6.1.3
`Cell-free Translation Systems 244
`4.6.2
`Enzymatic Peptide Synthesis
`247
`4.6.2.1
`Introduction 247
`4.6.2.2
`Approaches to Enzymatic Synthesis
`248
`4.6.2.3
`Manipulations to Suppress Competitive Reactions 250
`4.6.2.4
`Irreversible C–N Ligations by Mimicking Enzyme Specificity
`4.6.3
`Antibody-catalyzed Peptide Bond Formation 253
`4.7
`References 256
`
`251
`
`5
`5.1
`5.1.1
`5.1.2
`5.1.3
`5.1.3.1
`5.1.3.2
`5.2
`5.2.1
`5.2.1.1
`5.2.1.2
`5.2.2
`
`269
`
`Synthesis Concepts for Peptides and Proteins
`Strategy and Tactics 269
`Linear or Stepwise Synthesis
`269
`Segment Condensation or Convergent Synthesis
`Tactical Considerations 273
`Selected Protecting Group Schemes 273
`Preferred Coupling Techniques 276
`Synthesis in Solution 277
`Convergent Synthesis of Maximally Protected Segments
`The Sakakibara Approach to Protein Synthesis
`278
`Condensation of Lipophilic Segments
`280
`Convergent Synthesis of Minimally Protected Segments
`
`272
`
`277
`
`282
`
`MPI EXHIBIT 1067 PAGE 7
`
`MPI EXHIBIT 1067 PAGE 7
`
`

`

`Contents
`
`IX
`
`5.2.2.1
`5.2.2.2
`5.3
`5.3.1
`5.3.2
`5.3.2.1
`5.3.2.2
`5.3.3
`5.3.4
`5.3.4.1
`5.3.4.2
`5.4
`5.4.1
`5.4.2
`5.4.2.1
`5.4.2.2
`5.4.3
`5.5
`
`6
`6.1
`6.1.1
`6.1.2
`6.1.3
`6.2
`6.3
`6.4
`6.5
`6.6
`6.7
`
`7
`7.1
`7.2
`7.2.1
`7.2.2
`7.2.3
`7.2.4
`7.2.5
`7.3
`7.4
`7.4.1
`7.4.2
`7.4.3
`
`286
`
`Chemical Approaches 282
`Enzymatic Approaches 284
`Optimized Strategies on Polymeric Support
`Stepwise SPPS 286
`Convergent SPPS 288
`Solid-phase Synthesis of Protected Segments
`289
`Solid Support-mediated Segment Condensation 290
`Phase Change Synthesis
`292
`Soluble-Handle Approaches 293
`Picolyl Ester Method 293
`Liquid-Phase Method 293
`Ligation of Unprotected Peptide Segments
`Backbone-engineered Ligation 295
`Prior Capture-mediated Ligation 297
`Template-mediated Ligation 297
`Native Chemical Ligation 298
`Biochemical Protein Ligation 304
`References 306
`
`294
`
`311
`
`319
`
`Synthesis of Special Peptides and Peptide Conjugates
`Cyclopeptides 311
`Backbone Cyclization (Head-to-Tail Cyclization)
`313
`Side Chain-to-Head and Tail-to-Side Chain Cyclizations
`Side Chain-to-Side Chain Cyclizations
`319
`Cystine Peptides 320
`Glycopeptides
`322
`Phosphopeptides
`329
`Lipopeptides 331
`Sulfated Peptides 333
`References 334
`
`339
`
`Peptide and Protein Design, Pseudopeptides, and Peptidomimetics
`Peptide Design 340
`Modified Peptides 345
`Side-Chain Modification 345
`Backbone Modification 348
`Combined Modification (Global Restriction) Approaches 350
`Modification by Secondary Structure Mimetics 352
`Transition State Inhibitors 353
`Peptidomimetics 354
`Pseudobiopolymers 357
`Peptoids 358
`Peptide Nucleic Acids (PNA)
`360
`b-Peptides, Hydrazino Peptides, Aminoxy Peptides,
`and Oligosulfonamides 361
`
`MPI EXHIBIT 1067 PAGE 8
`
`MPI EXHIBIT 1067 PAGE 8
`
`

`

`X
`
`Contents
`
`7.4.4
`7.4.5
`7.5
`7.5.1
`7.5.2
`7.5.3
`7.6
`
`8
`8.1
`8.1.1
`8.1.2
`8.1.3
`
`8.1.4
`8.1.5
`8.2
`8.2.1
`8.2.2
`8.2.3
`8.2.4
`8.2.5
`8.3
`
`9
`9.1
`9.1.1
`9.1.2
`9.1.3
`9.1.3.1
`9.1.3.2
`9.1.3.3
`9.1.3.4
`9.2
`9.3
`9.3.1
`9.3.2
`9.3.3
`9.3.3.1
`9.3.3.2
`9.3.3.3
`9.4
`
`Oligocarbamates 362
`Oligopyrrolinones 363
`Macropeptides and De-novo Design of Peptides and Proteins 364
`Protein Design 364
`Peptide Dendrimers 369
`Peptide Polymers
`371
`References 372
`
`379
`
`Combinatorial Peptide Synthesis
`Parallel Synthesis
`382
`Synthesis in Teabags 383
`Synthesis on Polyethylene Pins (Multipin Synthesis)
`Parallel Synthesis of Single Compounds on Cellulose
`or Polymer Strips
`385
`Light-Directed, Spatially Addressable Parallel Synthesis
`Liquid-Phase Synthesis using Soluble Polymeric Support
`Synthesis of Mixtures 389
`Reagent Mixture Method 389
`Split and Combine Method 390
`Encoding Methods 392
`Peptide Library Deconvolution 396
`Biological Methods for the Synthesis of Peptide Libraries 397
`References 399
`
`384
`
`387
`388
`
`403
`
`Application of Peptides and Proteins
`Protein Pharmaceuticals
`403
`Importance and Sources 403
`Endogenous Pharmaceutical Proteins 404
`Engineering of Therapeutic Proteins
`406
`Peptide-Based Vaccines 407
`Monoclonal Antibodies 407
`Protein Pharmaceuticals with Various Functions 409
`Future Perspectives 410
`Large-Scale Peptide Synthesis
`Peptide Pharmaceuticals
`416
`Peptide Drugs and Drug Candidates 416
`Peptide Drug Delivery Systems
`419
`Peptides as Tools in Drug Discovery 421
`Peptides Targeted to Functional Sites of Proteins 422
`Peptides Used in Target Validation 423
`Peptides as Surrogate Ligands for HTS 424
`References 425
`
`412
`
`Glossary
`
`429
`
`Index
`
`545
`
`MPI EXHIBIT 1067 PAGE 9
`
`MPI EXHIBIT 1067 PAGE 9
`
`

`

`Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`XI
`
`Preface
`
`The past decades have witnessed an enormous development in peptide chemistry
`with regard not only to the isolation, synthesis, structure identification, and eluci-
`dation of the mode of action of peptides, but also to their application as tools
`within the life sciences. Peptides have proved to be of interest not only in bio-
`chemistry, but also in chemistry, biology, pharmacology, medicinal chemistry, bio-
`technology, and gene technology.
`These important natural products span a broad range with respect to their com-
`plexity. As the different amino acids are connected via peptide bonds to produce a
`peptide or a protein, then many different sequences are possible – depending on
`the number of different building blocks and on the length of the peptide. As all
`peptides display a high degree of conformational diversity, it follows that many di-
`verse and highly specific structures can be observed.
`Whilst many previously published monographs have dealt exclusively with the
`synthetic aspects of peptide chemistry, this new book also covers its biological as-
`pects, as well as related areas of peptidomimetics and combinatorial chemistry.
`The book is based on a monograph which was produced in the German language
`by Hans-Dieter Jakubke: Peptide, Chemie und Biologie (Spektrum Akademischer
`Verlag, Heidelberg, Berlin, Oxford), and first published in 1996. In this new publi-
`cation, much of the material has been completely reorganized and many very re-
`cently investigated aspects and topics have been added. We have made every effort
`to produce a practically new book, in a modern format, in order to provide the
`reader with profound and detailed knowledge of this field of research. The glos-
`sary, which takes the form of a concise encyclopedia, contains data on more than
`500 physiologically active peptides and proteins, and comprises about 20% of the
`book’s content.
`Our book covers many different issues of peptide chemistry and biology, and is
`devoted to those students and scientists from many different disciplines who
`might seek quick reference to an essential point. In this way it provides the read-
`er with concise, up-to-date information, as well as including many new references
`for those who wish to obtain a deeper insight into any particular issue. In this
`book, the “virtual barrier” between peptides and proteins has been eliminated be-
`cause, from the viewpoint of the synthesis or biological function of these com-
`pounds, such a barrier does not exist.
`
`MPI EXHIBIT 1067 PAGE 10
`
`MPI EXHIBIT 1067 PAGE 10
`
`

`

`XII
`
`Preface
`
`This monograph represents a personal view of the authors on peptide chemis-
`try and biology. We are aware however that, despite all our efforts, it is impossible
`to include all aspects of peptide research in one volume. We are not under the il-
`lusion that the text, although carefully prepared, is completely free of errors. In-
`deed, some colleagues and readers might feel that the choice of priorities, the
`treatment of different aspects of peptide research, or the depth of presentation
`may not always be as expected. In any case, comments, criticisms and sugges-
`tions are appreciated and highly welcome for further editions.
`Several people have contributed considerably to the manuscript. All the graphi-
`cal material was prepared by Dr. Katherina Stembera, who also typed large sec-
`tions of the manuscript, provided valuable comments, and carried out all the for-
`matting. We appreciate the kindness of Professor Robert Bruce Merrifield, Dr.
`Bernhard Streb and Dr. Rainer Obermeier for providing photographic material for
`our book. Margot Müller and Helga Niermann typed parts of the text. Dr. Frank
`Schumann and Dr. Jörg Schröder contributed Figures 2.19 and 2.25, respectively.
`We also thank Dirk Bächle, Kai Jenssen, Micha Jost, Dr. Jörg Schröder and Ulf
`Strijowski for comments and proofreading parts of the manuscript.
`Dr. Gudrun Walter, Maike Petersen, Dr. Bill Down, and Hans-Jörg Maier took
`care that the manuscript was converted into this book in a rather short period of
`time, without complications.
`
`Bielefeld
`and
`Dresden-Langebrück
`April 2002
`
`Norbert Sewald
`
`Hans-Dieter Jakubke
`
`MPI EXHIBIT 1067 PAGE 11
`
`MPI EXHIBIT 1067 PAGE 11
`
`

`

`Peptides: Chemistry and Biology. Norbert Sewald, Hans-Dieter Jakubke
`Copyright © 2002 Wiley-VCH Verlag GmbH & Co. KGaA
`ISBNs: 3-527-30405-3 (Hardback); 3-527-60068-X (Electronic)
`
`XIII
`
`Abbreviations
`
`aa
`AA
`Aad
`bAad
`AAP
`aatRS
`Ab
`Abu
`A2bu
`Abz
`Ac
`ACE
`AChR
`Acm
`ACP
`ACTH
`AD
`Ada
`Adoc
`ADP
`Aet
`Ag
`AGaloc
`AGE
`AGloc
`AGRP
`Ahx
`eAhx
`AHZ
`Aib
`AIDS
`AIle (aIle)
`AKH
`
`amino acid
`antamanide (anti-amanita peptide)
`2-aminoadipic acid
`3-aminoadipic acid
`antimicrobial animal peptides
`amino-acyl tRNA synthetase
`antibody
`aminobutyric acid
`2,4-diaminobutyric acid
`aminobenzoic acid
`acetyl
`angiotensin-converting enzyme
`acetylcholine receptor
`acetamidomethyl
`acyl carrier protein
`corticotropin
`Alzheimer’s disease
`adamantyl
`adamantyloxycarbonyl
`adenosine diphosphate
`aminoethyl
`antigen
`tetra-O-acetyl-b-D-galactopyranosyloxycarbonyl
`advanced glycation end products
`tetra-O-acetyl-D-glucopyranosyloxycarbonyl
`agouti-related protein
`2-aminohexanoic acid (norleucine)
`6-aminohexanoic acid
`alanyl-histidinato zinc (b)
`a-aminoisobutyric acid
`acquired immune deficiency syndrome
`alloisoleucine
`adipokinetic hormone
`
`MPI EXHIBIT 1067 PAGE 12
`
`MPI EXHIBIT 1067 PAGE 12
`
`

`

`XIV
`
`Abbreviations
`
`Al
`Ala
`bAla
`Aloc
`Alom
`AMP
`AM-PS
`ANF
`ANP
`Ans
`Aoc
`AOE
`AOP
`
`Apa
`APM
`Apm
`AQP
`Ar
`Arg
`Asn
`Asp
`Ab
`Asu
`At
`AT
`ATP
`AVP
`
`Bac5
`BAL
`BBB
`Bet
`BGloc
`BGP
`BHA
`Bip
`BK
`BLP
`BMP
`BNP
`Boc
`BOI
`
`Bom
`
`allyl (used only in 3-letter code names)
`alanine
`b-alanine
`allyloxycarbonyl
`allyloxymethyl
`adenosine monophosphate
`aminomethyl polystyrene
`atrial natriuretic factor
`atrial natriuretic peptide
`anthracene-9-sulfonyl
`1-azabicyclo[3.3.0]octane-2-carboxylic acid
`(S)-2-amino-8-oxo-(S)-9,10-epoxidecanoic acid
`7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexa-
`fluorophosphate 1)
`6-aminopenicillanic acid
`aspartame
`2-aminopimelic acid
`aquaporin
`aryl
`arginine
`asparagine
`aspartic acid
`amyloid-b
`aminosuberic acid
`azabenzotriazolyl
`angiotensin
`adenosine triphosphate
`8-arginine-vasopressin
`
`bactenecin
`backbone amide linker
`blood brain barrier
`a-betainyl
`tetrabenzylglucosyloxycarbonyl
`bone Gla protein
`benzhydrylamine
`biphenyl-4-sulfonyl
`bradykinin
`bombinin-like peptide
`brain morphogenetic protein
`brain natriuretic peptide
`tert-butoxycarbonyl
`2-[(1H-benzotriazol-1-yl)oxy]-1,3-dimethylimidazolidinium hexa-
`fluorophosphate
`benzyloxymethyl
`
`MPI EXHIBIT 1067 PAGE 13
`
`MPI EXHIBIT 1067 PAGE 13
`
`

`

`Abbreviations XV
`
`BOP
`
`Bpoc
`BPTI
`BroP
`BSA
`Bsmoc
`Bspoc
`Bt
`Btb
`Btm
`Bu
`tBu
`Bum
`Bz
`Bzl
`Bzl(4-Me)
`
`CADD
`CaM
`Cam
`CAMD
`CAMM
`cAMP
`CBD
`CCAP
`CCK
`CD
`CD4
`CD8
`cDNA
`CDR
`CE
`CF3-BOP
`
`CF3-HBTU
`
`CF3-PyBOP
`
`CG
`Cg
`cGMP
`CGRP
`Cha
`Cho
`
`benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluo-
`rophosphate
`2-(biphenyl-4-yl)prop-2-yloxycarbonyl
`basic pancreatic trypsin inhibitor
`bromotris(dimethylamino)phosphonium hexafluorophosphate
`bovine serum albumin
`1,1-dioxobenzo[b]thiophen-2-ylmethoxycarbonyl
`2-(tert-butylsulfonyl)-2-propenyloxycarbonyl
`(benzylsulfanylmethyl)
`1-tert-butoxycarbonyl-2,3,4,5-tetrachlorobenzoyl
`benzylsulfanylmethyl (benzylthiomethyl)
`butyl
`tert-butyl
`tert-butoxymethyl
`benzoyl
`benzyl (Bn in contemporary organic synthesis)
`4-methylbenzyl
`
`computer-aided drug design
`calmodulin
`carboxamidomethyl (carbamoylmethyl, aminocarbonylmethyl)
`computer-aided molecular design
`computer-assisted molecular modeling
`cyclic AMP
`chitin binding domain
`crustacean cardioactive peptide
`cholecystokinin
`circular dichroism
`cell surface glycoprotein 4
`cell surface glycoprotein 8
`complementary DNA
`complementary determining region
`capillary electrophoresis
`6-(trifluoromethyl)benzotriazol-1-yloxytris(dimethylamino)-
`phosphonium hexafluorophosphate
`2-[6-(trifluoromethyl)benzotriazol-1-yl]-1,1,3,3-tetramethyluro-
`nium hexafluorophosphate 2)
`6-(trifluoromethyl)benzotriazol-1-yloxytripyrrolidinophospho-
`nium hexafluorophosphate
`chorionic gonadotropin
`chromogranin
`cyclic guanosine monophosphate
`calcitonin gene related peptide
`cyclohexylalanine
`choline
`
`MPI EXHIBIT 1067 PAGE 14
`
`MPI EXHIBIT 1067 PAGE 14
`
`

`

`XVI
`
`Abbreviations
`
`cHp
`CID
`CIEF
`Cit
`CJD
`2,6-Cl2Bzl
`CLIP
`Clt-Cl
`CLTR
`Cm
`CM
`CN
`CNBr
`Cne
`CNP
`CNS
`cOc
`COSY
`Cpa
`CP
`cPe
`CPP
`CPS
`CRF
`CRIF
`CRL
`CsA
`CSF
`CSPPS
`CST
`CT
`Cy
`Cya
`Cyp
`Cys
`(Cys)2
`CZE
`
`Dab
`DABCO
`DABSCL
`DABITC
`DAG
`DAST
`DBF
`
`cycloheptyl
`chemically ionized desorption
`capillary isoelectric focusing
`citrulline
`Creutzfeldt Jakob disease
`2,6-dichlorobenzyl
`corticotropin-like intermediate lobe peptide
`2-chlorotritylchloride
`2-chlorotrityl resin
`carboxymethyl
`casomorphin or chorionic mammotropin
`calcineurin
`cyanogen bromide
`2-cyanoethyl
`C-type natriuretic peptide
`central nervous system
`cyclooctyl
`correlated NMR spectroscopy
`4-chlorophenylalanine
`carboxypeptidase
`cyclopentyl
`cell-penetrating peptide
`convergent peptide synthesis
`corticotropin releasing factor
`corticotropin release-inhibiting factor
`cerulein
`cyclosporin A
`colony stimulating factor
`convergent solid-phase peptide synthesis
`cortistatin
`calcitonin or charge-transfer
`cyclohexyl
`cysteic acid
`cyclophilin
`cysteine
`cystine
`capillary zone electrophoresis
`
`a,c-diaminobutyric acid
`1,4-diazabicyclo[2.2.2]octane
`4-(dimethylamino)azobenzene-4'-sulfonyl chloride
`4-(dimethylamino)azobenzene-4'-isothiocyanate
`diacylglycerol
`N,N-diethylaminosulfur trifluoride
`dibenzofulvene
`
`MPI EXHIBIT 1067 PAGE 15
`
`MPI EXHIBIT 1067 PAGE 15
`
`

`

`Abbreviations XVII
`
`DBIP
`DBU
`Dcb
`DCC
`DCHA
`DCM
`DCME
`Dcp
`DCU
`DDAVP
`Dde
`Ddz
`DEA
`DEAE
`Deg
`DEPBT
`DEPC
`DFIH
`
`Dha
`Dhbt
`DIC
`DIPEA
`DKP
`DMA
`Dmab
`
`DMAE
`DMAP
`2,4-Dmb
`3,4-Dmb
`DMBHA
`DMF
`Dmh
`Dmp
`DMS
`DMSO
`Dmt
`DNA
`Dnp
`Dns
`Doc
`DOPA
`Dpa
`Dpg
`
`diazepam-binding inhibitor peptide
`1,8-diazabicyclo[5.4.0]undec-7-ene
`dichlorobenzyl
`N,N'-dicyclohexylcarbodiimide
`dicyclohexylamine
`dichloromethane
`dichloromethyl methyl ether
`a,a-dicyclopropylglycine
`N,N'-dicyclohexylurea
`[1-deamino,D-Arg8]vasopressin
`1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl
`a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl
`diethylamine
`diethylaminoethanol
`Ca,a-diethylglycine
`3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one
`diethyl pyrocarbonate
`2-fluoro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluoro-
`phosphate
`a,b-didehydroalanine (more commonly, a,b-dehydroalanine)
`3,4-dihydro-4-oxobenzotriazin-3-yl
`N,N'-diisopropylcarbodiimide
`diisopropylethylamine
`diketopiperazine
`dimethylacetamide
`4-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]ami-
`no}benzyl
`2-(dimethylamino)ethanol
`4-(dimethylamino)pyridine
`2,4-dimethoxybenzyl
`3,4-dimethoxybenzyl
`dimethoxybenzhydrylamine
`N,N-dimethylformamide
`2,6-dimethylhept-4-yl
`2,4-dimethoxyphenyl
`dimethyl sulfide
`dimethyl sulfoxide
`2',6'-dimethyltyrosine
`deoxyribonucleic acid
`dinitrophenyl
`5-(dimethylamino)naphthalene-1-sulfonyl (dansyl)
`2,4-dimethylpent-3-yloxycarbonyl
`3,4-dihydroxyphenylalanine
`3,3-diphenylalanine
`Ca,a-diphenylglycine
`
`MPI EXHIBIT 1067 PAGE 16
`
`MPI EXHIBIT 1067 PAGE 16
`
`

`

`XVIII
`
`Abbreviations
`
`Dpm
`DPPA
`Dpr
`DPTU
`DSC
`DSIP
`DSK
`Dsu
`Dts
`DTT
`DVB
`Dyn
`
`E+
`<E
`EC
`ECD
`ECE
`ECEPP
`ECGF
`ECM
`ECP
`ED50
`EDC
`EDF
`EDFR
`EDT
`EDTA
`EEDQ
`EF
`EGF
`EH
`ELAM
`ELH
`ELISA
`EM
`EMIT
`EMSA
`ENK
`EPL
`EPO
`EPR
`ER
`ES
`ESI-MS
`
`diphenylmethyl (benzhydryl)
`diphenyl phosphorazidate
`2,3-diaminopropionic acid
`N,N'-diphenylthiourea
`di(N-succinimidyl)carbonate
`delta sleep-inducing peptide
`drosulfakinin
`(2S,7S)-2,7-diaminosuberic acid
`dithiasuccinyl
`dithiothreitol
`divinylbenzene
`dynorphin
`
`electrophile (or E-X)
`pyroglutamic acid
`ethylcarbamoyl
`extracellular domain
`endothelin converting enzyme
`Empirical Conformational Energy Program for Peptides
`endothelial cell growth factor
`extracellular matrix
`ecdysteroid carrier protein
`median effective dosis
`N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
`epidermal growth factor or erythrocyte differentiation factor
`epidermal growth factor receptor
`ethanedithiol
`ethylenediaminetetraacetic acid
`ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate
`elongation factor
`epidermal growth factor
`eclosion hormone
`endothelial leukocyte adhesion molecule
`egg laying hormone
`enzyme linked immunosorbent assay
`electron microscopy
`enzyme multiplied immunoassay technology
`electrophoretic mobility shift assay
`enkephalin
`expressed protein ligation
`erythropoietin
`electron paramagnetic resonance
`endoplasmatic reticulum
`electrospray
`electrospray ionisation mass spectrometry
`
`MPI EXHIBIT 1067 PAGE 17
`
`MPI EXHIBIT 1067 PAGE 17
`
`

`

`Abbreviations XIX
`
`ES-MS
`ESR
`ET
`Et
`ETH
`Etm
`
`Fa
`Fab
`FAB-MS
`FACS
`FAD
`FADH2
`Farn
`FaRP
`Fbg
`Fc
`Fd
`FGF
`FITC
`FKBP
`Fm
`FMDV
`Fmoc
`FN
`For
`FP
`Fpa
`FPLC
`FPP
`FRET
`FRL
`FS
`FSF
`FSH
`FTase
`FTIR
`
`GABA
`Gal
`GalT
`GC
`gCSF
`GFC
`GFP
`
`electrospray mass spectrometry
`electron spin resonance
`endothelin
`ethyl
`ecdysis-triggering hormone
`ethoxymethyl
`
`3-(2-furyl)acryloyl
`antigen binding Ig fragment
`fast atom bombardment mass spectrometry
`fluorescence-activated cell sorter
`flavin adenine dinucleotide, oxidized form
`flavin adenine dinucleotide, reduced form
`farnesyl
`FMRFamide-related peptide
`fibrinogen
`ferrocenyl
`ferredoxin
`fibroblast growth factor
`fluoresceinyl isothiocyanate
`FK506 binding protein
`9-fluorenylmethyl
`foot-and-mouth disease virus
`9-fluorenylmethoxycarbonyl
`fibronectin
`formyl
`fluorescence polarisation
`4-fluorophenylalanine
`fast protein liquid chromatography
`farnesyl pyrophosphate
`fluorescence resonance energy transfer
`formin-related peptide
`follistatin
`fibrin-stabilizing factor
`follicle-stimulating hormone
`farnesyltransferase
`Fourier-transform infrared
`
`c-aminobutyric acid
`galanin, galactose
`galactosyl transferase
`gas chromatography
`granulocyte colony stimulating factor
`gel filtration chromatography
`green fluorescent protein
`
`MPI EXHIBIT 1067 PAGE 18
`
`MPI EXHIBIT 1067 PAGE 18
`
`

`

`XX
`
`Abbreviations
`
`GGTase
`GH
`GHRH
`GHRP
`GHS
`GHS-R
`GIP
`Gla
`GLC
`Glc
`GlcNAc
`Gln
`GLP
`Glu
`Gly
`GMP
`GnRH
`GPC
`GPCR
`GPI
`GRF
`GRP
`GRPP
`GSF
`GSH
`GSSG
`GT
`GTP
`Gva
`
`hXaa
`h
`HA
`HAL
`
`HAMDU
`
`HAMTU
`
`HAPipU
`
`HAPyTU
`
`HAPyU
`
`geranylgeranyltransferase
`growth hormone
`growth hormone releasing hormone
`growth hormone releasing peptide
`growth hormone secretagogue
`growth hormone secretagogue receptor
`gastric inhibitory polypeptide
`4-carboxyglutamic acid
`gas liquid chromatography
`glucosyl, glucose
`N-acetyl-D-glucosamine
`glutamine
`glucagon-like peptide
`glutamic acid
`glycine
`guanosine monophosphate
`gonadotropin releasing hormone
`gel permeation chromatography
`G-protein coupled receptor
`glycosylphosphatidylinositol or guinea pig ileum
`growth hormone releasing factor
`gastrin-releasing peptide
`glicentin-related pancreatic peptide
`glutathion-S-transferase
`glutathione reduced
`glutathione oxidized
`gastrin
`guanosine triphosphate
`d-guanidinovaleric acid
`
`homoamino acid
`human
`head activator
`5-(4-hydroxymethyl-3,5-dimethoxy)-valeric acid
`(derived hypersensitive acid-labile linker)
`O-(7-azabenzotriazol-1-yl)-1,3-dimethylimidazolidinium hexa-
`fluorophosphate 1)
`O-(7-azabenzotriazol-1-yl)-1,3-dimethyl-1,3-trimethyleneuronium
`hexafluorophosphate 1, 2)
`O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium
`hexafluorophosphate 1, 2)
`S-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)thiouronium
`hexafluorophosphate 1, 2)
`O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium
`hexafluorophosphate1, 2)
`
`MPI EXHIBIT 1067 PAGE 19
`
`MPI EXHIBIT 1067 PAGE 19
`
`

`

`hArg
`HATTU
`
`HATU
`
`HAV
`Hb
`HBMDU
`
`HBPyU
`
`HBsAg
`HBTU
`
`HBV
`Hbz
`Hci
`HCRT
`HCV
`hCys
`HDCOTU
`
`HDL
`HDTU
`
`Hep
`Hepes
`HEPP
`HF
`HFBA
`HFIP
`HG
`hGH
`HIC
`Hip
`His
`HIV
`HMB
`Hmb
`
`Abbreviations XXI
`
`homoarginine
`S-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylthiouronium hexa-
`fluorophosphate
`O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
`phosphate; correct IUPAC name: 1-[bis-(dimethylamino)methyli-
`umyl]-1H-1,2,3-triazolo[4,5-b]pyridin-3-oxide
`hexafluorophosphate or 1-[(dimethylamino)-(dimethyliminium)
`methyl]-1H-1,2,3-triazolo[4,5-b]pyridin-3-oxide
`hexafluorophosphate
`hepatitis A virus
`hemoglobin
`O-(benzotriazol-1-yl)-1,3-dimethyl-1,3-dimethyleneuronium hexa-
`fluorophosphate 2)
`O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexa-
`fluorophosphate 2)
`hepatitis B virus surface antigen
`2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
`phosphate 2);
`correct IUPAC name: 3-[Bis(dimethylamino)methyliumyl]-
`3H-benzotriazol-1-oxide hexafluorophosphate
`hepatitis B virus
`2-hydroxybenzyl
`homocitrulline
`hypocretin
`hepatitis C virus
`homocysteine
`O-(dicyanomethylenamino)-1,1,3,3-tetramethyluronium hexa-
`fluorophosphate
`high density lipoprotein
`O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyl-
`uronium hexafluorophosphate
`heptyl
`N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid
`human IgE pentapeptide
`hydrogen fluoride
`heptafluorobutyric acid
`hexafluoroisopropanol
`human little-gastrin
`human growth hormone
`hydrophobic interaction chromatography
`hippuryl, hippuric acid
`histidine
`human immunodeficiency virus
`hydroxymethylbenzoic acid
`2-hydroxy-4-methoxybenzyl
`
`MPI EXHIBIT 1067 PAGE 20
`
`MPI EXHIBIT 1067 PAGE 20
`
`

`

`XXII
`
`Abbreviations
`
`HMFS
`HMK
`HMP
`HMPA
`HMPAA
`HMPB
`HMPPA
`HMPT
`HMQC
`Hnb
`HOAt
`HOBt
`Hoc
`HOCt
`HODhbt
`HOPip
`HOPPipU
`
`HOSu
`HOTU
`
`HPCE
`HPLC
`Hpp
`HppTU
`
`HPSEC
`hPTH
`HpyClU
`HRMS
`HS
`HSA
`HSAB
`Hse
`Hsp
`HSPS
`HSV
`HTS
`HVE
`Hyp
`Hyv
`
`iBu
`IC
`iC
`
`N-[9-(hydroxymethyl)-2-fluorenyl]succinamic acid
`high molecular weight kininogen
`4-(hydroxymethyl)phenoxy
`hexamethylphosphoric triamide
`4-(hydroxymethyl)phenoxyacetic acid
`4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid
`3-[4-(hydroxymethyl)phenoxy]propanoic acid
`hexamethylphosphorous triamide
`heteronuclear multiple quantum coherence spectroscopy
`2-hydroxy-6-nitrobenzyl
`1-hydroxy-7-aza-1H-benzotriazole
`1-hydroxy-1H-benzotriazole
`cyclohexyloxycarbonyl
`ethyl 1-hydroxy-1H-1,2,3-triazole-4-carboxylate
`3-hydroxy-1,2,3-benzotriazin-4(3H)-one
`N-hydroxypiperidine
`2-[2-oxo-1(2H)pyridyl]-1,1,3,3-bis(pentamethylene)uronium hexa-
`fluorophosphate
`N-hydroxysuccinimide
`O-[(ethoxycarbonyl)cyanomethyleneamino]-1,1,3,3-tetramethyl-
`uronium hexafluorophosphate
`high performance capillary electrophoresis
`high performance liquid chromatography
`5-hydroxy-1-(4'-nitrophenyl)pyrazole
`2-[1-(4'-nitrophenyl)-1H-pyrazol-5-yl]-1,1,3,3-tetramethyluronium
`tetrafluoroborate
`high performance size exclusion chromatography
`human parathyroid hormone
`chloro-1,1,3,3-bis(tetramethylene)-uronium hexafluorophosphate
`high resolution mass spectrometry
`hymenstatin
`human serum albumin
`hard and soft acids and bases
`homoserine
`heat shock protein
`high speed peptide synthesis
`herpes simplex virus
`high-throughput screening
`high voltage electrophoresis
`hydroxyproline
`a-hydroxyisovaleric acid
`
`isobutyl
`inhibitory concentration
`isocapronic
`
`MPI EXHIBIT 1067 PAGE 21
`
`MPI EXHIBIT 1067 PAGE 21
`
`

`

`Abbreviations XXIII
`
`ICAM
`IEC
`IF
`IFN
`Ig
`IGF
`IHB
`IIDQ
`IL
`Ile
`im
`IMAC
`iMds
`in
`iNoc/iNOC
`Ioa
`IP
`Ipc
`IPL
`IPNS
`iPr
`IRaa
`IRMA
`IS-MS
`IU
`Iva
`IvDde
`
`kB
`kDa
`KGF
`KM
`
`Lac
`Lan
`L