Peptide synthesis automated

Robert Bruce Merrifield (1921-2006) was born in Fori Worth, Texas, anti received his Ph.D. at the University oi California, Los Angeles, in 1949. He then joined the faculty at the Rockefeller Institute, where he remained until his death. In 1984, he was awarded the Nobel Prize in chemistry for his development of methods for the automated synthesis of peptides. 

RB Merrifield, JM Stewart, N Jemberg. Instrument for automated synthesis of peptides. Anal Chem 38, 1905, 1966. 

JK Chang, M Shimuzu, S-S Wang. Fully automated synthesis of fully protected peptide hydrazides on recycling hydroxymethyl resin. J Org Chem 41, 3255, 1976. 

Peptides have many desirable properties as components of synthetic vectors. Peptide synthetic chemistry is well established, with the convenience of automated synthesis resulting in a well-defined, high-purity product of low toxicity and immunogenicity for in vivo use. Furthermore, even short peptides of 7 to 30 amino acids can accommodate enormous structural diversity, functionality, and combinations of properties. 

This strategy using rapid automated synthesis of libraries of peptides and fluorescent screening of reactivity has allowed Miller to identify specific peptide-catalysts for specific applications such as the KR of an intermediate en route to an aziridomi-tosane [165,169], the KR of certain fert-alcohols [166], the regioselective acylation of carbohydrates [168], and finally the KR of AT-acylated fert-amino alcohols with s values from 19 to >50 (Scheme 21) [166],... 

For the direct use of tyrosine 0-sulfate in peptide synthesis a set of -protected Tyr(S03H) derivatives were synthesized that can be combined with the most common protection schemes. In addition to Z-Tyr(S03Ba1/2)-0Ba1/2 (11)[3S1 (see Section 6.6.1.1.4), the related Boc and Fmoc derivatives have been synthesised as barium, sodium, potassium salts, and even as tetrabutylammonium salts due to their better solubility in solvents generally used for automated synthesis on solid supports.1152 154 155 ... 

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

The instrument chosen for the evaluation of carbohydrate synthesis was an ABI-433 peptide synthesizer (Fig. 2). The instrument was adapted for carbohydrate synthesis and customized coupling cycles were developed. A specially designed low-temperature reaction vessel was installed and interfaced with a commercially available cooling device.13 The necessary reagents were loaded onto the instrument ports and reaction conditions were programmed on the computer, in a fashion similar to the automated synthesis of peptides. 

Spot synthesis may be carried out manually, semi- or fully automated (see Fig. 1). Manual spot synthesis is convenient for the synthesis and screening of a relative small number of peptides (up to 100) and a large pipetting volume (>0.5 aL). For all other cases a semiautomated or fully automated synthesis is recommended. For synthesis of small spots with a pipetting volume of about 0.1 ptL, spot synthesizers from Intavis AG (Koln, Germany) are very useful (3). 

Gausepohl, H. and Behn, C. (2002) Automated synthesis of solid-phase bound peptides. In Peptide Arrays on Membrane Support, eds. J. Koch and M. Mahler, pp. 55-68. Berlin Springer-Verlag. 

Automated synthesis of peptide and oligonucleotide libraries was initiated about 10 years ago [4], Within the last three years, there has been much attention focused on the generation of combinatorial libraries of small molecules. As with biopolymers, the use of solid resin support was central to the advance of this field. In solid-phase synthesis, one of the reactants is covalently bound to the solid support and an excess of the other reactants may be used in each step to drive reactions to completion. Purification of the intermediates and final product is easily achieved through extensive washing of the resin after each chemical step. For the purpose of high throughput synthesis, cleavage of the final... 

Robey, F. A. and Fields, R. L. (1989) Automated synthesis of bromoacetyl-modi-fied peptides for preparation of synthetic peptide polymers, peptide-protein conjugates and cyclic peptides. Anal. Biochem. 177, 373-377. 

Resin Preparation for Automated Synthesis of Linear Peptides... 

Kuroda, N., Hattori, T., Fujioka, Y., Cork, D. G., Kitada, C., and Sugawara, T. (2001) Application of automated synthesis suite to parallel solution-phase peptide synthesis. Chem. Pharm. Bull. Tokyo 49, 1147-1154. 

Richter LS, Spellmeyer DC, Martin EJ, Figliozzi GM, Zuckermann RN. Automated synthesis of nonnatural oligomer h-braries the peptoid concept. Combinatorial Peptide and Nonpeptide Libraries. Jung G, ed. 1996. VCH, Weinheim, Germany, pp. 387 04. 

While the assembly of oligopeptides and oligonucleotides is routine and has become highly automated, the automated synthesis of oligosaccharides is still in its infancy despite some notable advances [82,83,84]. The situation becomes even more complex when the protecting group requirements for both the oligosaccharide assembly, and peptide assembly combine in the same molecule to stretch this aspect of chemical synthesis to its limits. Conse-... 

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