Peptides chemoselective bond

For glycopeptide synthesis, much attention has to be paid to the stereoselective formation of the natural-type glycosidic bond which must remain unchanged in the course of the synthesis. Therefore, in comparison to peptide synthesis, the compatibility and chemoselectivity of the applied reaction is fundamental in glycopeptide synthesis. 

Since this postsynthetic, chemoselective lipidation procedure bypasses all the difficulties encountered during preparative HPLC purification of lipopeptides, the a-hydrazinoacetyl peptides were further developed into a strategy of lipidation by chemoselective hydrazone formation between lipophilic glyoxaldehyde vectors and prepurified hydrazino peptides (Scheme 10).11241 The hydrazino handle can be located at the N-termini or even at preselected lysine side-chain positions. Various lipophilic vectors were proposed containing one or more fatty acids coupled via amides to spacers which in turn are linked to glyoxylic acid via an amide bond.1124-1271... 

The chemoselective ligation approach of thioester bond formation for the preparation of complex peptides has been used in a straightforward, convenient synthesis of a four-helix-bundle TASP molecule. Due to unique, mutually reactive functionalities, i.e. a-COSH and BrCH2COOH, the reaction of the unprotected peptide fragments proceeds rapidly in aqueous solution to give a homogeneous product in high yield. 18 ... 

Another versatile chemoselective ligation method for the efficient synthesis of TASP[98] molecules is based on the rapid and selective reaction of thiols with activated double bonds, e.g. in a maleimide group (Scheme 17).[106-108] For this purpose, the cyclic decameric template is functionalized with four maleimide residues, which allow reaction with thiol-containing peptide fragments in aqueous solution. 

Small molecules or peptides are then chemoselectively conjugated to the ketone-modified macromolecular scaffold via the amino-oxy functional group to form an oxime bond (see Fig. 5). 

So far, the methods that have been shown to enable chemoselective peptide bond formation have relied upon the particular reactivity between thioesters and aminothiols. Almost simultaneously, Raines [36] and Bertozzi [37] reported a new method for the formation of a peptide bond with high chemoselectivity the so-called Staudinger ligation. This reaction had... 

This type of modified lipopeptide cannot be deblocked under basic conditions because the labile palmitic acid thioester group would be preferentially hydrolyzed. The C-terminus of the peptide chain was selectively deprotected by removing the choline ester with choline esterase without affecting the palmitic acid thioester bond. The observed chemoselectivity here is exactly opposite to that found in nonenzymatic conversions. Some of the synthesized N-terminally deprotected lipopeptides, have been labeled with biotinand are expected to serve as anchors for a protein moiety in an artificial membrane. Butyrylcholine esterase mediated cleavage of the choline ester has been utilized l as the key step in the synthesis of S-palmitoylated peptides such as Myr-Gly-Cys(Plm)-Thr-Leu-Ser-Ala-OH, which represents the characteristic N-terminus of the a-subunit of human G o protein. 

The first total synthesis of a protein by the chemical ligation approach utilized nonnative bonds at the site of ligation. In the early 1990s the Kent laboratory pioneered a thioester forming ligation that utilized a highly chemoselective reaction between a peptide with a C-terminal carbothioate group 1 and a N-terminal bromoacetyl peptide 2 at pH <4 (Scheme 2). 

The development of chemoselective reactions to give a native peptide bond at the site of hgation allows the synthesis of proteins with little or no modification to the covalent structure. A native structure at the ligation site is often desirable in the middle of protein structural domains (amino acid 60-120). The challenge of this approach is to form an amide bond chemoselectively in the presence of free amine side chains (Lys) and carboxylate side chains (Glu/Asp). Ideally, no protecting groups should be used for any of the amino acid side chains as they limit peptide solubility and require additional deprotection steps that can severely reduce the yield and convenience of the synthesis. 

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