Peptidyl ω-Asp Selenoesters Enable Efficient Synthesis of N-Linked Glycopeptides

Abstract

Chemical synthesis is an attractive approach allows for the assembly of homogeneous complex N-linked glycopeptides and glycoproteins, but the limited coupling efficiency between glycans and peptides hampered the synthesis and research in the related field. Herein we developed an alternative glycosylation to construct N-linked glycopeptide via efficient selenoester-assisted aminolysis, which employs the peptidyl ω-asparagine selenoester and unprotected glycosylamine to perform rapid amide-bond ligation. This glycosylation strategy is highly compatible with the free carboxylic acids and hydroxyl groups of peptides and carbohydrates, and readily available for the assembly of structure-defined homogeneous N-linked glycopeptides, such as segments derived from glycoprotein EPO and IL-5.

Recent Advances in Glycopeptide and Glycoprotein Synthesis: A Refined Synthetic Probe towards the Biological World

“…To improve the synthetic efficiency of convergent aspartylation, a modified aminolysis protocol was introduced using aspartyl active esters. [ 27‐28 ] Compared with the thio‐ or oxoester counterparts, aspartyl selenoesters demonstrated enhanced reactivity, among which the seleno‐phenyl ester afforded an optimal balance between high reactivity and sufficient stability. In particular, the selenoester‐mediated glycosylation takes place without additional coupling reagents or catalysts, and is highly compatible with free C‐terminal carboxylic acid, as well as multiple functional groups within the complex‐type sialylundecasaccharide.…”

Site Specific Preparation of N‐Glycosylated Peptides: Thioamide‐Directed Activation of Aspartate

“…In addition, activation of this aspartate side chain carboxyl group is commonly plagued by aspartimide formation [14] . Methods to provide chemoselectivity include the use of aspartate thioacid, [15] thioester [16] or selenoester‐containing [17] peptides. Selective amination of the modified aspartate provides the N‐ glycopeptides, though orthogonal protection is still required for site‐selective activation of the aspartate, and aspartimide formation remains an issue.…”

Chemical Synthesis of Homogeneous Human E-Cadherin N-Linked Glycopeptides: Stereoselective Convergent Glycosylation and Chemoselective Solid-Phase Aspartylation

“…The biological studies of N-glycosylation of E-cadherins often require well-defined N-glycopeptides, which however are difficult to acquire from natural sources due to their microheterogeneity. The developed chemical and enzymatic synthesis strategies, along with native chemical ligation (NCL), enabled the synthesis of complex N-glycopeptides and N-glycoproteins with significant biological importance. − However, those methods still suffer from poor stereoselective control and low efficiency …”