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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Der "Sewald/Jakubke" ist und bleibt das einzige moderne, auf dem neuesten wissenschaftlichen Stand gehaltene fortgeschrittene Lehrbuch der Peptid-Biochemie! Auch für diese zweite, um ein Viertel erweitere Auflage haben die Autoren Hunderte von Publikationen gelesen und zu einem informativen und vollständigen Überblick über das Fachgebiet zusammengefasst. Nach einer Einführung in die Grundlagen der Peptidstruktur und -synthese werden die wichtigsten Familien biologisch aktiver Peptide systematisch abgehandelt. Mit interdisziplinärem Anspruch werden dann wichtige Anwendungen aus der Biotechnologie, Pharmazie und Biomedizin besprochen. Selbstverständlich werden auch Themen der Spitzenforschung berücksichtigt, zum Beispiel Pseudopeptide, Peptidmimetika und Aspekte der kombinatorischen Synthese. -- Neu in dieser Auflage sind Fragen und Übungsaufgaben, die das Nacharbeiten von Vorlesungen oder das Selbststudium erleichtern.
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Seitenzahl: 1082
Veröffentlichungsjahr: 2015
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Table of Contents
Cover
Series
Title
Copyright
Preface to the second edition
Preface to the first edition
1: Introduction and Background
References
2: Fundamental Chemical and Structural Principles
2.1 Definitions and Main Conformational Features of the Peptide Bond
2.2 Building Blocks, Classification, and Nomenclature
2.3 Analysis of the Covalent Structure of Peptides and Proteins
2.4 Three-Dimensional Structure
2.5 Methods of Structural Analysis
2.6 Review Questions
References
3: Biology of Peptides
3.1 Historical Aspects and Biological Functions
3.2 Biosynthesis
3.3 Selected Biologically Active Peptides
3.4 Review Questions
References
4: Peptide Synthesis
4.1 Principles and Objectives
4.2 Protection of Functional Groups
4.3 Peptide Bond Formation
4.4 Racemization During Synthesis
4.5 Solid-Phase Peptide Synthesis (SPPS)
4.6 Biochemical Synthesis
4.7 Review Questions
References
5: Synthesis Concepts for Peptides and Proteins
5.1 Strategy and Tactics
5.2 Solution Phase Synthesis (SPS)
5.3 Solution Phase/Solid Phase-Hybrid Approaches
5.4 Optimized Strategies on a Polymeric Support
5.5 Chemical Ligation Strategies
5.6 Review Questions
References
6: Synthesis of Special Peptides and Peptide Conjugates
6.1 Cyclopeptides
6.2 Cystine Peptides
6.3 Glycopeptides
6.4 Phosphopeptides
6.5 Lipopeptides
6.6 Sulfated Peptides
6.7 Review Questions
References
7: Peptide and Protein Design, Pseudopeptides, and Peptidomimetics
7.1 Peptide Design
7.2 Modified Peptides
7.3 Peptidomimetics
7.4 Pseudobiopolymers
7.5 Macropeptides and de novo Design of Peptides and Proteins
7.6 Review Questions
References
8: Combinatorial Peptide Synthesis
8.1 Parallel Synthesis
8.2 Synthesis of Mixtures
8.3 Review Questions
References
9: Application of Peptides and Proteins
9.1 General Production Strategies
9.2 Improvement of the Therapeutic Potential
9.3 Protein Pharmaceuticals
9.4 Peptide Pharmaceuticals
9.5 Review Questions
References
10: Peptides in Proteomics
10.1 Genome and Proteome
10.2 Separation Methods
10.3 Peptide and Protein Analysis in Proteomics
10.4 Activity-Based Proteomics
10.5 Review Questions
References
Glossary
Index
Guide
Cover
Table of Contents
Begin Reading
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cover
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Peptides: Chemistry and Biology
Second, Revised and Updated Edition
Norbert Sewald
Hans-Dieter Jakubke
The Authors
Prof. Dr. Norbert Sewald
Bielefeld UniversityDepartment of ChemistryPO Box 10013133501 BielefeldGermanye-mail: [email protected]
Prof. em. Dr. Hans-Dieter Jakubke
Leipzig UniversityDepartment of BiochemistryPrivate address:Höntzschstr. 1a01465 LangebrückGermanye-mail: [email protected]
First Edition 2002
Second, Revised and Updated Edition 2009
All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
Library of Congress Card No.: applied for
British Library Cataloguing-in-Publication DataA catalogue record for this book is available from the British Library.
Bibliographic information published by the Deutsche NationalbibliothekDie Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.
© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a 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.
ISBN: 978-3-527-31867-4
Preface to the second edition
Peptides are continuously gaining increasing attention for application as lead compounds for the development of drugs, as drug molecules, as molecular tools for diagnostic purposes in biochemistry, medicinal sciences as well as proteome research. Since the first edition of this book has been published, a storming development in the peptide field took place. While formerly the development of synthetic methodology prevailed, currently peptide application in a biochemical, medicinal or analytical context predominates. Many different peptide conjugates have been tailored according to specific scientific questions.
The second thoroughly revised edition of this book especially takes into account these recent developments. Many sections have been updated carefully and some of them have been re-organized and extended significantly. This is especially true for Chapter 3, dealing with the biology of peptides, Chapter 5 that focuses on synthesis concepts for peptides and proteins, as well as Chapter 6 on special peptides and peptide conjugates. The recent developments of peptide drugs required an in-depth revision of Chapter 9 which is now an up to date reference on currently available peptide and protein therapeutics. The emerging role of peptides in an analytical context called for the addition of a new Chapter 10 providing details on the role of peptides on proteomics.
The second edition of our book also very much relies on advice, help and contributions by several colleagues. While it would lead too far to mention all of them, the most significant contributions have to be acknowledged in this preface. Chapter 2 was critically revised by Hans-Jörg Hofmann, University of Leipzig. The Section 6.2 was re-written by Luis Moroder, Max-Planck-Institute of Biochemistry, Martinsried. Dirk Ullmann and Volker Schellenberger usefully contributed to updating Chapter 9 on the application of peptides and proteins. Dr. Katherina Sewald prepared excellent graphical material and molecular formulae. Jens Conradi designed the new cover picture. Dr. Frank Weinreich, Lesley Belfit, Maike Peterson, Dr. Rosemary Whitelock, and Claudia Zschernitz, who were responsible for editing and production at Wiley-VCH, are acknowledged for carefully dealing with the manuscript and converting it into a book of high quality.
We very much hope that this second edition will meet the same positive response and enthusiastic comments by our colleagues as the first edition did.
Finally we would like to dedicate this book on Chemistry and Biology of Peptides to the memory of two pioneers in the field who favorably commented on the first edition, but passed away in the meantime: Robert B. Merrifield and Murray Goodman.
BielefeldandDresden-LangebrückAugust 2008
Norbert Sewald
Hans-Dieter Jakubke
Preface to the first edition
The past decades have witnessed an enormous development in peptide chemistry with regard not only to the isolation, synthesis, structure identification, and elucidation 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 biochemistry, but also in chemistry, biology, pharmacology, medicinal chemistry, biotechnology, and gene technology.
These important natural products span a broad range with respect to their complexity. 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 diverse 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 aspects, 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 publication, much of the material has been completely reorganized and many very recently 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 glossary, 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 reader 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 because, from the viewpoint of the synthesis or biological function of these compounds, such a barrier does not exist.
This monograph represents a personal view of the authors on peptide chemistry 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 illusion that the text, although carefully prepared, is completely free of errors. Indeed, 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 suggestions are appreciated and highly welcome for further editions.
Several people have contributed considerably to the manuscript. All the graphical material was prepared by Dr. Katherina Stembera, who also typed large sections of the manuscript, provided valuable comments, and carried out all the formatting. 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.
BielefeldandDresden-LangebrückApril 2002
Norbert Sewald
Hans-Dieter Jakubke
1Introduction and Background
Peptide research has experienced considerable development during the past few decades. The progress in this important discipline of natural product chemistry is reflected in a flood of scientific data. The number of scientific publications per year increased from about 10 000 in the year 1980 to presently more than 20 000 papers. The introduction of new international scientific journals in this research area reflects this remarkable development.
A very useful bibliography on peptide research was published by John H. Jones [1]. The Houben-Weyl sampler volume E 22 “Synthesis of Peptides and Peptidomimetics” edited by Murray Goodman (Editor-in-Chief), Arthur Felix, Luis Moroder and Claudio Toniolo [2] represents the most comprehensive general treatise in this field. This work is a tribute to the 100th aniversary of Emil Fischer’s first synthesis of peptides and is the successor of two Houben-Weyl volumes, in German, edited by Erich Wünsch in 1974 [3].
A number of very important physiological and biochemical functions of life are influenced by peptides. Peptides are involved as neurotransmitters, neuromodulators, and hormones in receptor-mediated signal transduction. More than 100 peptides with functions in the central and peripheral nervous systems, in immunological processes, in the cardiovascular system, and in the intestine are known. Peptides influence cell–cell communication upon interaction with receptors, and are involved in a number of biochemical processes, for example metabolism, pain, reproduction, and immune response.
The increasing knowledge of the manifold modes of action of bioactive peptides led to an increased interest of pharmacology and medical sciences in this class of compounds. The isolation and targeted application of these endogenous substances as potential intrinsic drugs are gaining importance for the treatment of pathologic processes. New therapeutic methods based on peptides for a series of diseases give rise to the hope that diseases, where peptides play a functional role, can be amenable to therapy.
Peptide chemistry contributes considerably to research in the life science area. Synthetic peptides serve as antigens to raise antibodies, as enzyme substrates to map the active site requirements of an enzyme under investigation, or as enzyme inhibitors to influence signaling pathways in biochemical research or pathologic processes in medical research. Peptide ligands immobilized to a solid matrix may facilitate specific protein purification. Protein–protein interaction can be manipulated by small synthetic peptides. The “peptide dissection approach” uses relatively short peptide fragments that are part of a protein sequence. The synthetic peptides are investigated for their ability to fold independently, with the aim to improve the knowledge on protein folding.
The isolation of peptides from natural sources, however, is often problematic. In many cases, the concentration of peptide mediators ranges from 10–15 to 10–12 mol per mg fresh weight of tissue. Therefore, only highly sensitive assay methods, such as immunohistochemical techniques, render cellular localization possible. Although not all relevant bioactive peptides occur in such low concentrations, isolation methods generally suffer from disadvantages, such as the limited availability of human tissue sources. Complicated logistics during collection or storage of the corresponding organs, e.g., porcine or bovine pancreas for insulin production, additionally impose difficulties on the utilization of natural sources. Possible contamination of tissue used for the isolation of therapeutic peptides and proteins with pathogenic viruses is an enormous health hazard. Factor VIII preparations for treatment of hemophilia patients, isolated from natural sources, have been contaminated with human immunodeficiency virus (HIV), while impure growth hormone preparations isolated from human hypophyses after autopsy have led to the transmission of central nerve system diseases (Creutzfeld–Jacob disease). Nowadays, many therapeutic peptides and proteins are produced by recombinant techniques. Immunological incompatibilities of peptide drugs obtained from animal sources have also been observed. Consequently, the development of processes for the synthesis of peptide drugs must be pursued with high priority.
Chemical peptide synthesis is the classical method which has been mainly developed during the past four decades, although the foundations were laid in the early 20th century by Theodor Curtius and Emil Fischer. Synthesis has often been the final structural proof of many peptides isolated only in minute amounts from natural sources.
The production of polypeptides and proteins by recombinant techniques has also contributed important progress in terms of methodology. Genetically engineered pharmaproteins verify the concept of therapy with endogenous protein drugs (endopharmaceuticals). Cardiovascular diseases, tumors, auto-immune diseases and infectious diseases are the most important indications. Classical peptide synthesis has, however, not been questioned by the emergence of these techniques. Small peptides, like the artificial sweetener aspartame (which has an annual production of more than 5000 tons), and peptides of medium size remain the objectives of classical synthesis, not to mention derivatives with nonproteinogenic amino acids or selectively labeled (13C, 15N) amino acid residues for structural investigations using nuclear magnetic resonance (NMR).
The demand for synthetic peptides in biological applications is steadily increasing. At present, following the sequencing of the human genome, peptides have become a focus of biotechnological research. Their importance is growing as they represent the essential bioactive molecules inside the biological systems. The research fields of genomics and proteomics generate a huge number of new peptide targets which can help combat diseases and strengthen the immune resistance. The new targets do not allow for an isolated position of peptide chemistry exclusively oriented toward synthesis. Modern interdisciplinary science and research require synthesis, analysis, isolation, structure determination, conformational analysis and molecular modeling as integrated components of a cooperation between biologists, biochemists, pharmacologists, medical scientists, biophysicists, and bioinformaticians. Studies on structure–activity relationships (SAR) involve a large number of synthetic peptide analogues with sequence variation and the introduction of nonproteinogenic buildings blocks. The ingenious concept of solid-phase peptide synthesis has exerted considerable impact on the life sciences, whilst methods of combinatorial peptide synthesis allow the simultaneous creation of peptide libraries which contain at least several hundred different peptides. The high yields and purities enable both in vitro and in vivo screening of biological activity to be carried out. Special techniques enable the creation of peptide libraries that contain several hundred thousand peptides; these techniques offer an interesting approach in the screening of new lead structures in pharmaceutical developments.
Peptide drugs, however, can be applied therapeutically only to a limited extent because of their chemical and enzymatic labilities. Many peptides are inactive when applied orally, and even parenteral application (intravenous or subcutaneous injection) is often not efficient because proteolytic degradation occurs on the locus of the application. However, sophisticated formulation techniques are very encouraging as they are capable of significantly enhancing the oral bioavailability of discovered active peptides. Application via mucous membranes (e.g., nasal) is promising. Despite the utilization of special depot formulations and new applications systems (computer-programmed minipump implants, iontophoretic methods, etc.) a major strategy in peptide chemistry is directed towards chemical modification in order to increase its chemical and enzymatic stability, to prolong the time of action, and to increase activity and selectivity towards the receptor.
The synthesis of analogues of bioactive peptides with unusual amino acid building blocks, linker or spacer molecules and modified peptide bonds is directed towards the development of potent agonists and antagonists of endogenous peptides. Once the amino acids of a protein that are essential for the specific biological mode of action have been revealed, these pharmacophoric groups may be incorporated into a small peptide. The development of orally active drugs is an important target. Rational drug design has contributed extensively in the development of protease-resistant structural variants of endogenous peptides, and in this context the incorporation of D-amino acids, the modification of covalent bonds, and the formation of ring structures (cyclopeptides) must be mentioned.
Peptidomimetics imitate bioactive peptides. The original peptide structure can hardly be recognized in these molecules, which induce a physiological effect by specific interaction with the corresponding receptor. Hence, a peptide structure may be transformed into a nonpeptide drug. This task is another timely challenge for peptide chemists, because only sufficient knowledge of the biologically active conformation of a peptide drug and of the interaction with the specific receptor enable the rational design of such peptide mimetics.
Today nearly 300 new peptide-based drugs for broad indications like cardiovascular diseases, bone metabolism disorders, type II diabetes and viral infections are at different stages of development. A breakthrough for peptides as important pharmaceuticals was the discovery of the 36-peptide enfuvirtide (T20; Fuzeon™) which is capable of docking on the surface of the AIDS virus and therefore blocking the virus from entering into human blood cells. The discovery of T20 has initiated research on viral entry inhibitors that form a new class of antiviral drugs.T20 is the first peptide-based drug to be produced on a metric ton scale by solid-phase peptide synthesis.
Interestingly, nanotubular structures based on cyclic tri-β-peptides have been synthesized that could be used in molecular electronic devives. Functional material from peptides promotes the development of nanotubular systems with interior and exterior functionalization which will widen the scope of these nanotubular structures to medical chemistry.
The variety of the tasks described herein renders peptide research an important and attractive discipline of modern life sciences. Despite the development of gene technology, peptide chemistry will have excellent future prospects because gene technology and peptide chemistry are complementary approaches.
References
1 J. H. Jones, J. Pept. Sci. 2000, 6, 201.
2 M. Goodman, A. Felix, L. Moroder, C. Toniolo, Synthesis of Peptides and Peptidomimetics in Houben-Weyl-Methoden der organischen Chemie, Vol. E22, K. H. Büchel (Ed.), Thieme, Stuttgart, 2002.
3 E. Wünsch, Synthese von Peptiden, in Houben-Weyl Methoden der organischen Chemie, Vol. 15, 1/2, E. Müller (Ed.), Thieme, Stuttgart, 1974.
