Peptide synthetic methods

Blaha, K. Linear Peptides Synthetic Methods Wade, R. Linear Peptides Synthesis and Structure — Activity Relationships Wieland, T., Birr, C. Homodetic Cyclic Peptides, in Amino Acids, Peptides and Related Compounds, International Review of Science, Vol. 6 (ed. Rydon, H. N.), p. 73, 97, 183, Butterworths, London 1976... 

This led further to preliminary computer assisted planning study of the synthesis of a variety of proteins, such as the A chain of insulin, by a combination of conventional peptide synthetic methods and stereoselective four component condensations which revealed that, for the latter, there are approximately 139,000,000 syntheses of the above-mentioned type, differing widely with respect to yield expectations andnumber of required steps. 12) Although it would be beyond the capabilities of the presently available advanced computers to generate and compare all of these conceivable pathways according to suitable criteria, it took only a few minutes of computing... 

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

New developments in chemistry can arise from the planning and testing of new synthetic methods. In contemporary chemistry, we can see developments whose roots can be found in biological processes, as the terms signal recognition , replication , autocatalysis or self-replication indicate. Modern ideas in these areas can be found in laboratories where work on peptide chemistry is being carried out. 

S. Beranova-Giorgianni and D. M. Desiderio. Fast Atom Bombardment Mass Spectrometry of Synthetic Peptides. In Methods in Enzymology Solid-Phase Peptide Synthesis, ed. G. B. Fields. Methods in Enzymology 289. Academic Press, San Diego, 1997, 478-499. 

For such an integrated research activity, differently modified peptides and proteins that carry modifications whose structure can be changed at will through synthesis are invaluable tools. Therefore, the synthesis of the lipidated peptides is an important theme. Lipidated peptides can typically not be accessed via standardized peptide synthesis methods. However, employing the synthetic tools developed and presented here, most types of lipidated peptides can now be synthesized and obtained in pure form. Even though solution-phase approaches still play a significant role in the synthesis of lipidated peptides, the recently developed solid-phase synthesis methods delineate the preferred strategy to access the majority of the required lipidated peptides. 

DKPs, and 2,6-DKPs can be distinguished on the basis of intramolecular C-N cyclization, tandem reactions, and synthetic methods used. 2,3-DKPs have been used in medicinal chemistry and are found in natural products such as antibiotics (piperacillin), cefoperazone, and bicyclomycin. 2,5-DKPs are common namrally occurring peptide derivatives and are frequently generated as unwanted by-products in the synthesis of oligopeptides. " ... 

The synthesis and utility of fluoroolefin peptide isosteres has previously been reviewed [45], The fluoroolefin isostere preparations summarized below are organized by the synthetic method employed to introduce the fluoroolefin rather than by the dipeptide isostere formed. 

G. Jung, A.G. Beck-Sickinger, Multiple peptide synthesis methods and their applications. New synthetic methods (87), Angew. Chem. Int. Ed. 31(4) (1992) 367-486. 

In view of the large diversity of structures listed in Tables 1 and 2, only the synthetic methods developed for the most common and biologically most important peptide derivatives will be discussed in the following sections. Additional attention will be paid to the often-ingenious design of artificial modifications capable of mimicking the native peptide transformations in an efficient and biologically competent manner. 

With respect to synthetic methods, the most thoroughly investigated lanthionine from the group of alkylated lanthionines is threo-3-methyllanthionine (2), a lanthionine which is also found in a number of natural peptides such as nisin[12l and epidermin.14 In this section, some of the synthetic methods are compared and discussed with respect to their relative applicability and their possible extension to other alkylated lanthionines. 

The sulfur extrusion method 21 has been extensively investigated for the synthesis of threo-3-methyllanthionine 25 however, in this case desulfurization was not used to generate the amino acid (either in free or protected form), but rather to form different sulfide-bridged cyclic peptides as precursors for the total synthesis of nisin (3). Development of synthetic methods in this area was particularly important in respect to the synthesis of nisin, since this lantibiotic contains four // eo-3-methyllanthionine residues. The synthesis proceeded from a protected f/zreo-3-methyl-D-cysteine in the N-terminal position and L-cysteine in the C-terminal position. 

Nisin, because of its continued use as a preservative for more than 30 years 661 became an obvious target for a total synthesis 13 To date, it remains the only naturally occurring lanthionine peptide for which this feat has been achieved. In contrast to the lanthionine peptide syntheses of most other approaches already discussed, the total synthesis of nisin is based on a solution-synthesis strategy. Whilst, the total synthesis of the pentacyclic, 34-residue peptide nisin also demonstrated that such syntheses are not a commercially viable option for large amounts of lantibiotics, they have opened the way to useful synthetic methods for the synthesis of novel conformationally constrained peptides and peptidomimetic compounds. 

It was observed that for CCK and related peptides sulfation of the tyrosine residue is essential for triggering the full hormonal response.131 32 More recently, additional sulfated peptides have been identified as CCK-58, 135 phytosulfokinine-a, as peptide growth factor in plants 136 as well as various toxins from Conus venom. 137138 This observation has fostered intensive research to develop synthetic methods for efficient production of tyrosine O-sulfated peptides by chemical and enzymatic approaches. 

In addition to the synthetic challenge of natural cyclic peptides, these compounds are often isolated in very low yields and thus their structure cannot always be determined without ambiguity. Consequently, total synthesis represents the safest way to prove their constitution, configuration, and even biological activity, since frequently this results from highly active minor contaminants. 10-12 Moreover, synthesis of the natural compounds allows for structural variations as required for structure-activity relationship (SAR) studies to identify the important pharmacophores and their orientation in space. Herein the reader is not provided with a comprehensive overview of the vast list of different natural cyclic peptides, but rather directed to comprehensive reviews. 1,13 Nonetheless, some important and characteristic representative members will be reported in the context of the synthetic methods. 

Three main categories of processes are used for the synthesis of peptides chemical synthesis, extraction from natural substances, and biosynthesis. On further scrutiny, almost 10 distinct synthetic methods can be distinguished (see Table 4.2). For the synthesis of some peptides, more than one method is used, including chemical (solution or solid phase) synthesis and recombinant biotechnology for salmon calcitonin, extraction from pancreas, semisynthesis, and recombinant biotechnology for insulin. 

In preparing these various libraries, extensive use is made of solid phase synthetic methods. These methods are all derived from the solid phase peptide synthesis (SPPS) method developed by Merrifield in 1963. When performing a large number of syntheses, it is preferable to perform the synthetic steps on a solid bead rather than completing the entire synthesis in the solution phase. The solid-phase technique makes byproduct removal and final compound purification easier. The organic chemistry literature contains a wealth of different types of solid-phase supports and novel linkers for attaching the synthetic substrate to the bead. 

Some attempts to reduce sodium chloride intake have been carried out. The first is to use some socUum chloride substitutes. Pottasium chloride is widely used for this purpose. However, pottasium chloride is not thought as perfect sodium chloride substitute because it contains bitter taste. Okai and his associates have synthesized several salty peptides (5). These peptides are expected to be good for hypertension, gestosis, diabetes mellitus and other deseases because they contain no sodium ions. These peptides, however, are not expected to be used as sodium chloride substitutes immediately because of the difficulty of in their synthesis and their cost. Although they are struggling to establish a new synthetic method of peptides in a mass production system with reasonable costs and to improve the salty potency of peptides, they have not dissolved this problem. Since the threshold value of ionic taste is around 1 mM regardless their kinds, it seems to be very difficult to prepare an artificial sodium... 

Today, it is well-known that peptides or proteins exhibit various kinds of taste. Our group has been researching on the relationship between taste and structure of peptides, BPIa (Bitter peptide la, Arg-Gly-Pro-Pro-Phe-Ile-Val) (7 as a bitter peptide, Om-p-Ala-HCl (OBA), Om-Tau-HCl as salty peptides(2j, and "Inverted-Aspartame-Type Sweetener" (Ac-Phe-Lys-OH) as a sweet peptide(5). The relationship between taste and chemical structure was partly made clear. Since commercial demand for these flavor peptides is increasing, we need to develop new synthetic methods which can prepare these peptides in large scale. We developed the following two methods (1) protein recombination method as a chemical method, (2) enzymatic synthesis using chemically modified enzyme as a biochemical method. 

Flavor notes and products of lipid oxidation in cooked meats, 85,86/ Flavor peptides convenient synthesis, 149-156 enzymatic synthesis, 151,154-156 protein recombination synthetic method, 149... 

Several synthetic methods are available for the preparation of Fc peptide conjugates, of which the active ester method is most compatible with biological environments.41 This method works under mild conditions with an isolable FcCO-active ester, in which reactive heterocyclic isolable esters are formed. These can be isolated or reacted in situ with suitable peptides to give the desired Fc-peptide conjugate. These active esters can be used as stoichiometric Fc delivery reagents, which make them suitable for automated solid-phase synthesis of Fc-peptide conjugates. 

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