Chemistry
Peptide Synthesis
Peptide synthesis is the chemical process of creating peptides, which are short chains of amino acids. This can be achieved through solid-phase synthesis or liquid-phase synthesis. In solid-phase synthesis, the peptide is built on a solid support, while in liquid-phase synthesis, the peptide is assembled in solution. Peptide synthesis is important in the production of pharmaceuticals, research, and biotechnology.
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10 Key excerpts on "Peptide Synthesis"
eBook - ePub- Stein(Author)
- 2017(Publication Date)
- CRC Press(Publisher)
An understanding of the relationship of a peptide or protein structure to its function is essential for the rational design of molecules with predicted properties that can be exploited for research and in the clinic. The chemical synthesis of peptides has a fundamental role in this area of modern biological research. Systematic variations in structure can be correlated with the properties of the resultant molecules; a direct approach to the identification of functional domains or of specific amino acids having specialized roles in the molecule of interest. These efforts are critically important since there is not yet a full appreciation of how the amino acid sequence of a peptide or protein directs its proper folding into a preferred bioactive conformation or a precise three-dimensional structure, giving rise to its unique properties. Macromolecular interactions, and the mechanisms governing biorecognition, particularly ligand/receptor interactions, must also be understood in order to design structures with predicted properties, and chemically synthesized peptides contribute to this goal as well. These and other applications of peptides have depended in large measure upon the accessibility of purified synthetic peptides ever since the first synthesis, in 1953, of a biologically active peptide hormone by du Vigneaud and his co-workers. The hormone was the cyclic octapeptide, oxytocin. Recent advances in the technology of chemical Peptide Synthesis, purification, and structural analysis have made such molecules more generally available, and the use of peptides in biomedical research and pharmaceutical development is expanding rapidly.BACKGROUNDThe term polypeptide was proposed in 1906 by Emil Fischer to describe structures consisting of variable numbers of amino acids linked together by amide bonds. The basic structural features of a linear peptide are illustrated in Figure 1 . A peptide bond is formed by a condensation reaction between two amino acids; the carboxyl group of one amino acid forms an amide bond with the amino group of a second amino acid, and a molecule of water is eliminated. The amino acids, which are called residues when they occur in peptide linkage, are conventionally numbered consecutively starting at the amino (N) terminus. The repetitive peptide backbone, which is all of the molecule except for the side-chain (R) groups, is defined by its length and by its direction. Each amino acid residue is distinguished by its side-chain moiety, which is attached to the alpha carbon atom (Fig. 1
- Lars Hovgaard, Sven Frokjaer, Marco van de Weert, Lars Hovgaard, Sven Frokjaer, Marco van de Weert(Authors)
- 2012(Publication Date)
- CRC Press(Publisher)
1 1 Peptide Synthesis Knud J. Jensen 1.1 INTRODUCTION Synthetic peptides are ubiquitous in biology, biomedicine, drug discovery, and many other fields. Chemically synthesized peptides serve very diverse purposes, includ-ing as biopharmaceutical drugs and for epitope mapping, peptide microarrays, and vaccine development. While proteins are generally prepared by recombinant meth-ods, chemical synthesis is the prevailing method for the preparation of peptides. This is due to the ease, predictability, and flexibility of chemical synthesis, which also allows the convenient incorporation of many nonproteinogenic modifications. Peptide Synthesis has allowed the preparation of numerous peptides, both on a labo-ratory scale and on a ton scale. However, there are also limitations—or current limi-tations, if you will—and having an understanding of the possibilities as well as the limitations will allow the biomedical users to better incorporate synthetic peptides in their research and applications. This chapter will provide an introduction to some of the most common methods in solid-phase Peptide Synthesis (SPPS), but will also briefly introduce solution synthesis of peptides and some other methods. CONTENTS 1.1 Introduction ...................................................................................................... 1 1.2 Protecting Groups ............................................................................................. 3 1.3 Solid-Phase Peptide Synthesis .......................................................................... 3 1.4 N α -Amino Protecting Groups: Boc versus Fmoc ............................................. 5 1.5 Side-Chain Protecting Groups .......................................................................... 6 1.6 Coupling Reagents ............................................................................................ 7 1.7 Amino Acids and Peptide Sequences That Spell Trouble ................................
eBook - PDF- Ulo Langel, Benjamin F. Cravatt, Astrid Graslund, N.G.H. von Heijne, Matjaz Zorko, Tiit Land, Sherry Niessen(Authors)
- 2009(Publication Date)
- CRC Press(Publisher)
199 15 Chemical Synthesis of Peptides and Proteins Ülo Langel The technique of chemical Peptide Synthesis goes back more than 100 years. Ever since the natural peptide structure became available, scientists have been eager to copy Nature and make synthetic peptides in their laboratories. Milestones of early peptide chemistry are the first synthesis of a protected peptide by the azide method (Curtius, 1881); first diPeptide Synthesis by chloranhydride method (Fischer, 1901) and synthesis of an 18-amino-acid-long peptide with sequence LG 3 LG 3 LG 9 (Fischer, 1907); introduction of Cbz and tert-butyloxycarbonyl ( t -Boc) protective groups (Bergmann and Zervas, 1932; Carpino, 1957); synthesis of first bioactive peptides glutathi-one and carnosine (1935) and oxytocin (1953, Nobel prize to du Vigneaud in 1955). The modern era in Peptide Synthesis started with Bruce Merrifield’s (1921– 2006) work in 1959 introducing the idea of solid phase Peptide Synthesis CONTENTS 15.1 Solid Phase Peptide Synthesis .................................................................... 200 15.2 Coupling and Activation: Rapid In Situ Protocols ...................................... 201 15.3 Protection Group Strategy ........................................................................... 201 15.4 Orthogonal Schemes for Protection ............................................................ 203 15.5 Side Reactions in SPPS ............................................................................... 204 15.5.1 Incomplete Acylation/Deprotection ............................................... 204 15.5.2 Racemization ................................................................................. 205 15.5.3 Undesired Cyclization ................................................................... 205 15.5.4 Alkylation .......................................................................................
eBook - PDFAdvanced Chemical Biology
Chemical Dissection and Reprogramming of Biological Systems
- Howard C. Hang, Matthew R. Pratt, Jennifer A. Prescher, Howard C. Hang, Matthew R. Pratt, Jennifer A. Prescher(Authors)
- 2023(Publication Date)
- Wiley-VCH(Publisher)
135 7 Peptide Synthesis and Engineering Gordon C. Brown and Paramjit S. Arora New York University, Department of Chemistry, 100 Washington Square East, New York, NY 10003, USA 7.1 Introduction Nearly all ribosomally synthesized proteins are com- posed of 20 common α-amino acids. All of these amino acids except glycine are monosubstituted at the α carbon and are therefore chiral with L-stereochemistry. By con- vention, amino acids are denoted with single-letter and three-letter codes (Table 7.1). These simple notations allow rapid exchange of peptide sequence information among practitioners. The three-letter codes predom- inantly correspond to the first three letters of each amino acid; the one-letter abbreviations were conceived by Dayhoff [3], who is considered a founder of the field of bioinformatics. By convention, peptide and protein sequences are written in the N (amino termi- nus) to C (carboxy terminus) direction as illustrated in Figure 7.1. 7.2 Peptide Synthesis Cellular Peptide Synthesis is an enzymatically con- trolled process, which occurs on the ribosome via sequential amide bond condensation reactions between amino acid-charged tRNAs. The ribosome is able to catalyze this disfavored reaction between an amine and a carboxylic acid with high fidelity, in the presence of a variety of side-chain functionalities while preserv- ing the stereochemical integrity at the C α position. In many ways, the ribosome carries out idealized Peptide Synthesis, since it (i) is catalytic with in situ activation of the incoming amino-acyl carboxylate, (ii) produces only water as a by-product, (iii) occurs in aqueous solution, and (iv) does not require the use of protecting groups. Chemical Peptide Synthesis is a highly optimized branch of synthetic organic chemistry.
eBook - PDFAmino Acids and Peptides
Volume 17
- J H Jones(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
Of recent years, however, the Japanese Peptide Symposia, which were originally estab- lished for domestic purposes, have acquired an international flavour, and their proceedings have been published in English since 1976, opening up Japanese peptide chemistry to the rest of the world in a most welcome manner. Graham Barrett has contributed the annual chapter on amino acids to these Reports now for twelve successive years, and is uniquely qualified by his experi- ence and exhaustive study of recent literature to edit an authoritative treatise on the subject. This he has now done: personally contributing key chapters on synthesis, resolution, and chemical reactions. The book has twenty-two chapters in all, covering chemical, biochemical, analytical, and structural aspects of all kinds of amino acids. It gives convenient rapid access to the literature of the last two decades, and is an indispensable sequel to Greenstein and Winitz (1961): Bodanszky and Ondetti ( 1 966)1° and its successor Bodanszky, Klausner, and Ondetti (1976)” have done much to shape the chemical thinking behind many of the achievements of Peptide Synthesis in the last twenty years. They are now superseded by M. Bodanszky ’s ‘Principles of Peptide Synthesis’ ( 1984),’3 an admirable account, although the critical reader will find a few details of fact and interpretation to quibble over. Its companion volume can be accorded a less ’ ‘Recent Advances in the Chemistry of 0-Lactam Antibiotics’, Proc. 3rd Int. Symp., Cambridge, U.K., 1984, ed. A. G. Brown and S. M. Roberts, Special Publication No. 52, The Royal Society of Chemistry, London, 1985. Peptides, Structure and Function’, Proc. 8th Am. Pept. Symp., Tucson, Arizona, 1983, ed. V. J. Hruby and D. H. Rich, Pierce, Rockford, Illinois, 1983. “Peptides 1984’, Proc. 18th Eur. Pept. Symp., Djuronaset, Sweden, 1984, ed. U. Rag- narsson, Almqvist and Wiksell International, Stockholm, 1984.
eBook - PDFAmino Acids, Peptides and Proteins
Volume 35
- J S Davies(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
Proteins, 2006, 35 , vii–xii 2.5 Peptide Bond Formation 78 2.6 Peptide Synthesis on Macromolecular Supports and Methods of Combinatorial Synthesis 83 2.7 Enzyme-mediated Synthesis and Semi-synthesis 88 2.8 Miscellaneous Reactions Related to Peptide Synthesis 90 3 Appendix: A List of Syntheses in 2002 91 3.1 Natural Peptides, Proteins and Partial Sequences 91 3.2 Sequential Oligo-and Poly-peptides 95 3.3 Enzyme Substrates and Inhibitors 96 3.4 Conformations of Synthetic Peptides 97 3.5 Glycopeptides 99 3.6 Phosphopeptides and Related Compounds 101 3.7 Immunogenic and Immunosuppressant Peptides 101 3.8 Nucleopeptides, PNAs 101 3.9 Miscellaneous Peptides 102 3.10 Purification Methods 104 References 104 Analogue and Conformational Studies on Peptides, Hormones and Other Biologically Active Peptides 129 Botond Penke, Ga ´bor To ´th and Gyo ¨rgyi Va ´radi 1 Introduction 129 2 Peptide Backbone Modifications and Peptide Mimetics 129 2.1 Aza, Oxazole, Oxazoline, Triazole, Triazine and Tetrazole Peptides 130 2.2 C [CH Q CH], C [Z-CF Q CH], C [CH(OH)–CH 2 ], C [CH(OH)–CH 2 –NH], retro-and retro-inverso-C [NHCH(CF 3 )], C [CH 2 O], retro-C [CONR], C [CO– N(NPht)], C [O–CO–N], C [CO–NR–O], C [CH 2 NH], C [CO–CH 2 -cyclopropyl-NH], C [PO 2 R–N], C [PO 2 R], C [NHCO] 131 2.3 Rigid Amino Acid, Peptide and Turn Mimetics 136 3 Cyclic Peptides 152 4 Biologically Active Peptides 157 4.1 Peptides Involved in Alzheimer’s Disease 157 4.2 Antimicrobial Peptides 161 4.3 ACTH peptides 168 4.4 Angiotensin II Analogues and Non-peptide Angiotensin II Receptor Ligands 168 4.5 Bombesin/Neuromedin Analogues 170 4.6 Bradykinin Analogues 171 4.7 Cholecystokinin Analogues, Growth Hormone-Releasing Peptide and Analogues 173 ix Amino Acids, Pept. Proteins, 2006, 35 , vii–xii
eBook - PDFAmino Acids, Peptides and Proteins
Volume 36
- J S Davies(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Typeset by Macmillan India Ltd, Bangalore, India Printed by Henry Ling Ltd, Dorchester, Dorset, UK If you buy this title on standing order, you will be given FREE access to the chapters online. Please contact [email protected] with proof of purchase to arrange access to be set up. Thank you Preface DOI: 10.1039/b710329h Dr Geoffrey Young, as editor of the first volume in this series in 1968, commented that ‘one could hardly ask for a more exciting time at which to review the field’. As a Chapter author, since those early days, I have seen the exciting times continue and the many volumes in this series have been party to great developments in the field. Solid phase synthesis, in its infancy in 1968, has revolutionised the making and manufacturing of peptides and no doubt the number and complexity of the peptides being made these days can only have been dreamt of 40 years ago. The availability of cloned proteins has made available molecular receptors, that now can routinely be used in molecular recognition studies, so that the development of efficient inhibitors has a much more rational basis. The principles of solid phase Peptide Synthesis have spawned not only a new approach to enhancing the pool of peptides available, but also the discipline of combinatorial chemistry. Numerous novel amino acids have been identified, and research in molecular recognition has increased the demand for novel non-proteinogenic amino acids. Thus developments in asymmetric synthesis have found excellent opportunities in the amino acid context, whose syntheses now depend less on the traditional resolution of synthesised racemates.
eBook - PDFAmino Acids and Peptides
Volume 21
- J H Jones(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
Some new sections to Appendix I have been included. There is a great interest in designing peptides and analogues with specific secondary structures especially in the search for new peptide- based drugs. Likewise there is a surge of interest in the production of antibodies, especially in the mapping of linear epitopes. These topics now have separate sections ( 4 . 4 and 4 . 6 ) in Appendix I. The locations of the bulk of the literature on Peptide Synthesis are much as they were last year’. Nevertheless, the contribution made by chemists and biochemists in the U.K. to Peptide Synthesis is shrinking steadily. Although two R.S.C. 74 Peptide Synthesis 75 .journals are amongst the more important vehicles for reporting new successes in Peptide Synthesis , the authors are frequently not U.K. scientists. The prevalence of automatic peptide synthesizers has led to the propagation of the uninformed view that Peptide Synthesis involves only pushing a button and this has perhaps deterred young scientists from becoming involved. In addition, old age and death have taken their toll in recent years, but this should not inhibit research effort: Old'agehath yet his honour and his toil; Death closes all: but something ere the end, Some work of noble note, may yet be done, Not unbecoming men that strove with GodsZ. If this hope is to be realized,the underfunding of relevant research councils and the contraction of British universities will have to be halted and hopefully reversed. Indeed, if this Specialist Report survives for another decade in the present climate, the mother tongue of the majority of its readers may well not be English or its derivatives.
eBook - PDFAmino Acids and Peptides
Volume 24
- J S Davies(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
199 1 , 14. 1409. H.Watanabe, K.Sugahara, K.Inoue, Y.Fujita, and H.Kodama. J.CIiroimtogr., 1991, 568, 445. X.Huang and W.T.Kok, J.Liy,Chi*otiimtogr., 1991, 14, 2207. T.Miyazawa, H.Iwanaga, T.Yamada, and S.Kuwata, Cheiii.E.-press, 1991. 6, 887. D.Yuan and D.J.Pietrzyk, J.Cliroiiiatogr., 1991, 557, 315. H.E.Meyer, E.Hoffmann-Posorske, H.Korte, A.Donella-Deana, A.M.Buanati, L . A. Pin na , J . Co u 11. J . Pe ric h , R . M . Valer i 0, and R . B.Johns , Cli r oniu t ogruphin, 1 990, 30, 69 1 . T.Bergman, B.Agerberth, and H.Joernvall, FEBS Lett., 1991. 283, 100. E.Leopold amd L.Gonesclou. Spectrli 2000, 1991, 156, 27. P.D.Hale, H.S.Lee, Y.Okamoto. and T.A.Skotheim, Ana/.Lrtt., 1991. 24, 345. B.A.Sela and R.Doolman, Cliti.Chini.Actcr, 1991, 203. 91. G.Marko-Varga, E.Dominguez. and M.Carlsson, GBF Moi7ogr., 1991, 14. 101. G.Marko-Varga, E.Dominguez, and M.Carlsson, GBF Monogr., 1991, 14, 165 (Chem.Ahs., 1992, 116, 79582). K.Kurkijarvi, T.Vierijoki, and T.Korpela, Awn. N . Y.A(mf.Sci.. 1990, 585, 394. 2 Peptide Synthesis BY D.T. ELMORE 1 Introduction The format of this report is the same as that used last year’. A new textbook on the chemical synthesis of peptides has been published2. Three are orientated towards peptide-based drugs, emphasizing the increasing importance of this multidisciplinary field. A plethora of other cover all aspects of the chemical and enzyme-catalysed synthe- sis of peptides. 2 Methods The arrangement of the main body of the report is identical to that used in recent years. 2.1.1 Amino-group protection - Automated equipment with artificial intelligence for the synthesis of N-(carboxyalky1)-amino acids has been described43.Three syntheses can be run in a working day with minimal manual intervention. The Boc group can be introduced by sonication of a mixture containing the amino acid, ( B O C ) ~ ~ and NaHC03 in suspension in ethanol or methanol44. Cessation of C 0 2 evolution provides a visual indication of the completion of reaction.
eBook - PDFAmino Acids and Peptides
Volume 20
- J H Jones(Author)
- 2007(Publication Date)
- Royal Society of Chemistry(Publisher)
It is claimed that the rate of coupling is similar to that with symmetrical acid anhydrides and that the products are pure. The growing importance of peptide-based drugs makes the synthesis of pseudopeptides by solid-phase methods highly desirable. Coy and his colleagues have developed a method for incorporating the -CH2NH- surrogate (reduced) peptide bond. A Boc-aminoaldehyde is allowed to condense with the terminal amino group of a peptide being assembled on a resin, and then the resultant Schiff base is reduced.149' 150 In spite of all the work that has gone into the design of linkers to ensure stability and freedom from side reactions during synthesis followed by detachment under mild conditions at the end of the synthesis, the perfect linker-matrix conjugate has not yet been produced. Little or no effort has been deployed to design linker-matrix conjugates that can be recycled, yet with syntheses being carried out on the kilo scale this must surely be an attractive goal. For those who can afford to work on this scale, there are chemical engineering problems that they should ~0nsider.l~'The small-scale synthesis of short peptides is a different world. Using the 'teabag' technique and the well-tried 152, 153 Merrifield methodology, Houghten has produced 250 new peptides in 3-4 weeks. The peptide productivity of the 'teabag' technique has already been considerably exceeded. By applying Merrifield's method with a polyacrylamide support grafted on small polyethylene rods, Geysen's group154 are able to produce 2000 small peptides in 10 working days. The peptides are obtained in 30-50 nmol quantities and are not further purified. Spot checks on the quantitative amino acid composition of particular peptides confirm the validity of the method.
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