Peptides chemical synthesis

An alternative approach to the production of subunit vaccines entails their direct chemical synthesis. Peptides identical in sequence to short stretches of pathogen-derived polypeptide antigens can be easily and economically synthesized. The feasibility of this approach was first verified in the 1960s, when a hexapeptide purified from the enzymatic digest of tobacco mosaic virus was found to confer limited immunological protection against subsequent administration of the intact virus. (The hexapeptide hapten was initially coupled to bovine serum albumin, used as a carrier to ensure an immunological response.)... 

The N-to-C assembly of the peptide chain is unfavorable for the chemical synthesis of peptides on solid supports. This strategy can be dismissed already for the single reason that repeated activation of the carboxyl ends on the growing peptide chain would lead to a much higher percentage of racemization. Several other more practical disadvantages also tend to disfavor this approach, and acid activation on the polymer support is usually only used in one-step fragment condensations (p. 241). 

Some six hundred structures of naturally occurring carbogenic molecules appe on the pages which follow, together with the name of each compound and references to the original literature of successful chemical synthesis. Thus, Part Three of this book is effectively a key to the literature of chemical synthesis as applied to the complex molecules of nature. The survey does not include oligomeric or polymeric structures, such as peptides, proteins, carbohydrates and polynucleotides, which fall outside the scope of this book because they can be assembled by repetitive procedures. 

A number of reactions of amino acids have become important in recent years because they are essential to the degradation, sequencing, and chemical synthesis of peptides and proteins. These reactions are discussed in Chapter 5. 

Chemical synthesis of natural cyclic peptides 97CRV2243. 

It is notable that small peptides were retained on a cross-linked PEI column [37] but polypeptides over 20 residues were weakly retained or not at all. Possibly, small peptides were able to penetrate into the depth of the bonded phase while larger peptides could not. These packings were more useful for the separation of oligonucleotides, i.e. more acidic compounds. Lawson et al. [39] have shown the applicability of PEI-silicas for assessing the purity of precursor blocks, monitoring the chemical synthesis and isolating reaction products after synthesis. 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

Jones J., The Chemical Synthesis of Peptides—International Series of Monographs on Chemistry, Oxford University Press, Oxford, 1994. 

ELPs can be produced via chemical synthesis and biosynthetically. For chemical synthesis via solid phase peptide synthesis, the attainable polymer length is limited, and if long polymers with a defined length are required then the biosynthetic approach is more appropriate. An advantage of chemical synthesis is, however, that it enables the facile introduction of functional residues in the polypeptide [27]. 

Bray BL (2003) Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov 2 587-593... 

Haase C, Seitz O (2007) Chemical Synthesis of Glycopeptides. 267 1-36 Hahn F, Schepers U (2007) Solid Phase Chemistry for the Directed Synthesis of Biologically Active Polyamine Analogs, Derivatives, and Conjugates. 278 135-208 Hansen SG, Skrydstrup T (2006) Modification of Amino Acids, Peptides, and Carbohydrates through Radical Chemistry. 264 135-162... 

Another, promising avenue to understand silk protein conformation and assembly is the use of model peptides. Although not recent (Fraser and MacRae, 1973 Lotz et al., 1974), studies of silk-based peptide from chemical synthesis, DNA recombinant technology, and computer simulation (Anderson et al., 1994 Asakura et al., 2003 Fahnestock et al., 2000 Fossey et al., 1991 Heslot, 1998 Kaplan, 1998 Wilson et al., 2000) have shown that selected repeats of silk proteins can be transformable hydrogels, elastomers, or regular thermoplastics and that with a proper design they can function as diverse molecular machines (Altman et al., 2003 Heslot, 1998 Kaplan, 1998 Urry, 1998). 

It has long been known that peptides of bacterial origin, such as N-formylat-ed oligopeptides, are potent activators of neutrophils. Bacterial protein biosynthesis is initiated by the codon AUG, which codes for polypeptide chains at the NH2 terminus to start with N-formylmethionine. However, very few mature bacterial proteins actually have this amino acid at the NH2 terminus because Af-formylmethionine is cleaved off by proteolytic processing. Sometimes just this amino acid is cleaved, but often several adjacent residues are also removed with it. These observations formed the basis for the chemical synthesis of a variety of N-formylated oligopeptides and an assessment of their ability to activate neutrophils in vitro. The most potent of these formylated peptides is TV-formylmethionyl-leucyl-phenylalanine (fMet-Leu-Phe). 

Jones, J. (1994) The Chemical Synthesis of Peptides. 230pp. Clarenden Press, Oxford. An authoritative account of peptide synthesis. 

JM Humphrey, AR Chamberlin. Chemical synthesis of natural product peptides coupling methods for the incorporation of noncoded amino acids into peptides. Chem Rev 97, 2243, 1997. 

Solid-phase peptide synthesis offers a fast and convenient route for many peptides when isotope-enriched compounds are not required. Classical synthesis additionally permits the use of non-natural amino acids and allows site-specific isotope labeling. Although Fmoc protected 15N-labeled amino adds are commercially available, the cost of such synthesis is usually prohibitive, and the peptides from chemical synthesis require perdeuterated detergents and unfortunately exclude investigation of internal dynamics through measurement of 15N relaxation. 

Some of the peptide families here have been successfully expressed in standard laboratory bacterial or yeast expression systems. This approach allows the production of larger amounts of peptides not amenable to chemical synthesis and opens the potential of large-scale production for biotechnological uses, for example, as plant protection agent applied externally. 

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