944412-75-3Relevant academic research and scientific papers
METHOD OF PREPARING GLYCOPEPTIDES
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, (2016/08/29)
A method is provided for the synthesis of glycopeptides using a sugar assisted ligation strategy, wherein an N-terminal peptide portion in the form of a thioester is coopled with a C-terminal peptide portion bearing a carbohydrate moiety comprising a thiol group.
Sugar-assisted ligation in glycoprotein synthesis
Yang, Yu-Ying,Ficht, Simon,Brik, Ashraf,Wong, Chi-Huey
, p. 7690 - 7701 (2008/02/09)
Sugar-assisted ligation (SAL) presents an attractive strategy for the synthesis of glycopeptides, including the synthesis of cysteine-free β-O-linked and N-linked glycopeptides. Here we extended the utility of SAL for the synthesis of α-O-linked glycopeptides and glycoproteins. In order to explore SAL in the context of glycoprotein synthesis, we developed a new chemical synthetic route for the α-O-linked glycoprotein diptericin ε. In the first stage of our synthesis, diptericin segment Cys(Acm) 37-Gly52 and segment Val53-Phe82 were assembled by SAL through a Gly-Val ligation junction. Subsequently, after Acm deprotection, diptericin segment Cys37-Phe82 was ligated to segment Asp1-Asn36 by means of native chemical ligation (NCL) to give the full sequence of diptericin ε. In the final synthetic step, hydrogenolysis was applied to remove the thiol handle from the sugar moiety with the concomitant conversion of mutated Cys37 into the native alanine residue. In addition, we extended the applicability of SAL to the synthesis of glycopeptides containing cysteine residues by carrying out selective desulfurization of the sulfhydryl-modified sugar moiety in the presence of acetamidomethyl (Acm) protected cysteine residues. The results presented here demonstrated for the first time that SAL could be a general and useful tool in the chemical synthesis of glycoproteins.
Extended sugar-assisted glycopeptide ligations: Development, scope, and Applications
Payne, Richard J.,Ficht, Simon,Tang, Sishi,Brik, Ashraf,Yang, Yu-Ying,Case, David A.,Wong, Chi-Huey
, p. 13527 - 13536 (2008/09/17)
Recently, we reported the development of sugar-assisted ligation (SAL), a novel peptide ligation method for the synthesis of glycopeptides. After screening a large number of glycoprotein sequences in a glycoprotein database, it became evident that a large proportion (approximately 53%) of O-glycosylation sites contain amino acid residues that will not undergo SAL reactions. To overcome these inherent limitations and broaden the scope of the method we report here the development of an extended SAL method. Glycopeptides containing up to six amino acid extensions N-terminal to the glycosylated residue were shown to facilitate ligation reactions with peptide thioesters, and these products were isolated in good yields. Kinetic analysis was used to show that as glycopeptides were extended by further amino acid residues, ligation reactions became slower. This finding was rationalized by molecular dynamics simulations using AMBER9. These studies suggested a general trend whereby the proximal distance between the reactive sites of the thioester intermediate (the N-terminal amine and the carbonyl carbon of the thioester) increased as glycopeptides were extended, thus slowing down the ligation rate. Each of the extended SAL methods showed broad tolerance to a number of different amino acid combinations at the ligation junction. Re-evaluation of the glycoprotein database suggested that 95% of the O-linked glycosylation sites can now be utilized to facilitate SAL or extended SAL reactions. As such, this method represents an extremely valuable tool for the synthesis of naturally occurring glycopeptides and glycoproteins. To demonstrate the applicability of the method, extended SAL was successfully implemented in the synthesis of the starting unit of the cancer-associated MUC1 glycoprotein.
