The Synthesis of Peptides

The synthesis of peptide antagonists has greatiy aided in the development of knowledge of other neuropeptide systems as well. 

Synthesis of Peptide. There is continual progress ia the improvement of instmments and reagents for peptide synthesis, especially "soHd phase polymerization" (90) (see Proteins). This method is suitable for the synthesis of peptides with 20 30 amino acid units. 

During the synthesis of peptides that contain 4-methoxybenzyl-protected cysteine residues, sulfoxide formation may occur. These sulfoxides, when treated with HF/ anisole, form thiophenyl ethers that cannot be deprotected therefore, the peptides should be subjected to a reduction step prior to deprotection. ... 

R. B. Merrifield (Rockefeller, New York) development of methodology for the synthesis of peptides on a solid matrix. 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this purpose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. 

Tab. 2.1 Representative list of N-protected / -amino acids 14 used in the synthesis of/ -peptides...

Lloyd-Williams P, Albericio F, Giralt E (1997) Chemical approaches to the synthesis of peptides and proteins. CRC, Boca Raton... 

Watts, P., Wiles, C., Haswell, S. )., PoMBO-ViLiAR, E., Styring, P., The synthesis of peptides using micro reactors, Chem. Commun. (2001) 990-991. 

Palchetti I, Mascini M (2005) Electrochemical Adsorption Technique for Immobilization of Single-Stranded Oligonucleotides onto Carbon Screen-Printed Electrodes. 261 27-43 Pascal R, Boiteau L, Commeyras A (2005) From the Prebiotic Synthesis of a-Amino Acids Towards a Primitive Translation Apparatus for the Synthesis of Peptides. 259 69-122 Paulo A, see Santos I (2005) 252 45-84 Perez EM, see Leigh DA (2006) 265 185-208 Perret F, see Coleman AW (2007) 277 31-88 Perron H, see Coleman AW (2007) 277 31-88 Pianowski Z, see Winssinger N (2007) 278 311-342 Piestert F, see Gansauer A (2007) 279 25-52... 

Henkel B, Zeng W, Bayer E. 9-Hydroxy-9-(4-carboxyphenyl)xanthene- a new linker for the synthesis of peptide amides. Tetrahedron Lett 1997 38 3511-3512. 

Breipohl G, Knolle J, Stuber W. Synthesis and application of acid labile anchor groups for the synthesis of peptide amides by Fmoc-solid-phase peptide synthesis. Int J Peptide Protein Res 1989 34 262-267. 

Racemization studies in the synthesis of the tripeptide Z-Gly-Phe-Gly from Z-Gly-Phe and Gly-OC2H5 revealed that in THF at room temperature such racemization occurred to the extent of about 5%, in DMF at -10 °C, however, less than 0.5%. 53 103 In the synthesis of Boc-Val-Tyr-OC2H5 (50%) from Boc-Val and Tyr-OC2H5 with CDI, a small amount of 0-acylation of tyrosine (4%) also occurred in the dipeptide. 11] A V -Carbonyldibenzimidazole was found inferior to CDI in the synthesis of peptides because of poorer yields and more rigorous reaction conditions needed. 53... 

Besides CDI, other azolides such as A N -oxalyldiimidazole, AyST-carbonyldi-1,2,4-triazole, MN -oxalyldi-1,2,4-triazole, and phosphorous and phosphoric imidazolides have been used in the synthesis of peptide bonds, as displayed in Table 5-4. 

The SPOT-synthesis method also employs Fmoc chemistry but uses hydroxyl groups present on cellulose filter paper to derivatize and thereby immobilize (3-alanine groups onto the paper. After deprotection, the 13-alanine groups can be used as platforms for the synthesis of peptide arrays (Fig. 7.5) (Frank, 1992 Gausepohl et al., 1992). This method has been widely used for mapping antigen-antibody interactions as well as protein-DNA, protein-metal and other protein-protein interactions (Reineke et al., 2001). 

The minimal cell, as the simplest system which has all the required properties of life (metabolism, self-reproduction and the ability to evolve), is presently studied as part of a new research discipline synthetic biology. This includes subjects such as synthesis in branches of biological systems, for example, of new RNA species, new peptides and new nucleic acid analogues, as well as the synthesis of peptide nucleic acids. One example is the work of M. R. Ghadiri and G. von Kiedrowski on self-replication of oligonucleotides and oligopeptides (Luisi, 2006b). 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Watts P, Wiles C, Haswell SJ, Pombo-ViUar E, Styring P (2001) The Synthesis of Peptides Using Microreactors. Chem Comm 11 990-991 Watts P, Wiles C, Haswell S, Pombo-Villar E (2002a) Investigation of Racemi-sation in Peptide Synthesis within a Microreactor. Lab Chip 2 141-144 Watts P, Wiles C, Haswell S, Pombo-Villar E (2002b) Solution Phase Synthesis of Beta-Peptides Using Microreactors. Tetrahedron 58 5427-5439... 

Baxendale IR, Ley SV, Smith CD, Tranmer GK (2006d) A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols. J Chem Soc Chem Commun 4835-4837... 

Bernatowicz MS, Daniels SB, Koster H (1989) A comparison of acid-labile linkage agents for the synthesis of peptide C-terminal amides. Tetrahedron Lett 30 4645-4648... 

Carbodiimides are, in general, useful compounds for effecting certain dehydrative condensations, e.g., in the formation of amides, esters, and anhydrides. These two crystalline water-soluble carbodiimides are especially useful in the synthesis of peptides and in the modification of proteins. The excess of reagent and the co-product (the corresponding urea) are easily separated from products with limited solubility in water. The hydrochloride is best employed in nonaqueous solvents (methylene chloride, acetonitrile, dimethylformamide). The methiodide is relatively stable in neutral aqueous systems, and thus is recommended for those media. 

Goodman, M., Felix, A., Moroder, M and Toniolo, C. (Eds.) (2002). Houben-Weyl Methods of Organic Chemistry, Vol E22, Synthesis of Peptides and peptidomimetics. Vol E22a, The synthesis of peptides, 901pp. Goerg Thieme Verlag Methods with experimental procedures. 

Lloyd-Williams, R, Albericio, F. and Giralt, E. (1997) Chemical Approaches to the Synthesis of Peptides and Proteins. 367pp. CRC Press. The main focus is on large molecules, with 1343 references. 

F Weygand, P Huber, K Weiss. The synthesis of peptides with symmetrical anhydrides I. Z Naturforsch 22B, 1084, 1967. 

T Wieland, H Bernhard. On the synthesis of peptides. Part 3. The use of anhydrides of N-acylated amino acids and derivatives of inorganic acids. Ann Chem 572, 190, 1951. 

JE Zimmerman, GW Callahan. The effect of active ester components on racemization in the synthesis of peptides by the dicyclohexylcarbodiimide method. J Am Chem Soc 89, 7151, 1967. 

W Konig, R Geiger. A new method for the synthesis of peptides activation of the carboxyl group with dicyclohexylcarbodiimide and 1-hydroxybenzotriazoles. Chem Ber 103, 788, 1970. 

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