Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis

Title
Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis
Publication Date
2011
Author(s)
Wilkinson, Brendan
( author )
OrcID: https://orcid.org/0000-0003-1866-6540
Email: bwilkin7@une.edu.au
UNE Id une-id:bwilkin7
Chun, Candy K Y
Payne, Richard J
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
John Wiley & Sons, Inc
Place of publication
United States of America
DOI
10.1002/bip.21471
UNE publication id
une:20505
Abstract
MUC1 is a cell-surface, epithelial glycoprotein that forms an essential protective barrier of cells and serves to modulate intercellular communication. During cancer progression, the dysregulation of glycosyltransferases, which serve to elongate cell-surface glycans, leads to aberrant glycosylation patterns on this glycoprotein. This results in the presentation of well-characterized, tumorassociated carbohydrate antigens (TACAs) which represent important biomarkers for a range of epithelial cancers. The synthesis of well-defined, multivalent MUC1 glycopeptide constructs bearing TACAs therefore represents a viable opportunity for the development of cancer vaccine candidates. We report herein the synthesis of a glycopeptide thioester, comprising the full eicosapeptide variable number tandem repeat (VNTR) region of MUC1, which was prepared bearing multiple copies of the cancer-associated TN antigen. The glycopeptide thioester was prepared on the solid-phase using two different methods on 2-chlorotrityl chloride and sulfamylbutyryl resins. The solid-phase assembly on 2-chlorotrityl chloride resin, followed by thioesterification in solution, afforded the desired thioester in 4% yield over 41 linear steps. Likewise, the glycopeptide thioester was successfully prepared on sulfamylbutyryl resin using an activation and thiol-release strategy in a 9% isolated yield. The resulting peptide thioester was successfully ligated to a deprotected MUC1 glycopeptide using the direct aminolysis ligation to afford a 5.8 kDa, 40 amino acid MUC1 glycopeptide bearing 10 copies of the TN antigen. This work represents an important step toward the immunological evaluation of multivalent MUC1 constructs.
Link
Citation
Biopolymers, 96(2), p. 137-146
ISSN
1097-0282
0006-3525
Start page
137
End page
146

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