Solution-phase peptide

Sections 27 15 through 27 17 describe the chemistry associated with the protection and deprotection of ammo and carboxyl functions along with methods for peptide bond formation The focus m those sections is on solution phase peptide synthesis Section 27 18 shows how these methods are adapted to solid phase synthesis... 

This derivative was used to improve the solubility characteristic of an argininal semicarbazone for solution-phase peptide synthesis. 

The acylated peptides (Myr)GCX-Bimane 31 a-e (X = G, L, R, T, V), which are found in certain nonreceptor tyrosine kinases and ct-subunits of several heterotrimeric G-proteins, were synthesized in solution using common solution-phase peptide synthesis with X-myristoylglycine as a building block. These model peptides were used for acylation studies with palmitoyl-CoA in phospholipid vesicles at physiological pH. For such uncatalyzed spontaneous reactions only a modest molar excess of acyl donor species (2.5 1) was necessary. Unprotected side chains of threonine or serine are not interfering with this S-acylation (Scheme 14). 

A possibility to overcome the time-consuming solution-phase peptide synthesis, but avoiding specific synthetic problems that cannot be addressed on tbe solid support, is to follow a combined solution-/solid-pbase approach. In such an approach the majority of the peptide sequence is typically assembled on solid support, but critical steps are performed in solution. Below, some exemplary peptides are discussed. 

DKPs are simple and easy to obtain and are quite common by-products of synthetic, spontaneous, and biological formation pathways. DKP formation has been well documented as side reactions of solid-phase and solution-phase peptide synthesis. In addition, DKPs have been shown to be decomposition products of various peptides, proteins, and other commercial pharmaceuticals. Cyclic dipeptides were found to be present in solutions of human growth hormone, bradykinin, histerlin, and solutions of agents within the classes of penicillins and cephalosporins. " DKPs are also enzymatically synthesized in several protists and in members of the plant kingdom. Hydrolysates of proteins and polypeptides often contain these compounds and they are commonly isolated from yeasts, lichens, and fungi. ... 

A. General description Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Eptifibatide binds to the platelet receptor glycoprotein (gp) Ilb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophifized. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

Scheme 9 Solution-Phase Peptide Synthesis of HC1 H-Tyr-a-Saal-Phe-Leu-OMe[45l...

Solution-Phase Peptide Synthesis 1182 24-11 Solid-Phase Peptide Synthesis 1185 24-12 Classification of Proteins 1190... 

Bray, A. M., Maeji, N. J., and Geysen, H. M. (1990) The simultaneous multiple production of solution phase peptides assesment of the Geysen method of simultaneous peptide synthesis. Tetrahedron Lett. 31, 5811-5814. 

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. 

For the affinity column selection library, a solution-phase peptide library (a mixture) is loaded onto a column with an immobilized target protein. This method has been applied successfully to retrieve an antibody-specific binding peptide from a mixture of peptides. It also was reported to identify peptide motifs for SH2 domains and kinase domains of protein tyrosine kinases. 

This ester was developed for C-terminal amino acids during solution phase peptide synthesis. Purification of intermediates can be monitored colorimetrically or visually. Protection is achieved by reacting the sodium salt of the A/-protected amino acid with the bromoacetamide derivative to give the ester in 70-95% yield. Cleavage is... 

Problems in solution phase peptide synthesis have been largely overcome by the development of solid phase peptide synthesis (SPPS). The chemical principles of peptide link formation and peptide synthesis remain the same, but in SPPS the growing peptide chain is anchored to a solid phase resin, thereby easing the iterative process of peptide bond formation, removing the need for crystallisations and purifications after each step of the synthesis, and in some ways simplifying protection/deprotection problems. SPPS earned Bruce Merrifield a Nobel Prize in 1986, and has eased the technical challenges of peptide synthesis to the extent that the process can now be automated. 

Tee esters (OTce), R-CO-OCH2CHCL3, 2,2,2-trichloroethyl esters suitable for protection of the C-terminus in solution-phase peptide synthesis. They can be hydrolyzed under mild conditions that are compatible with acid-labile N -protecting groups [G. Just, K. Grozinger, Synthesis 1976, 457]. 

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