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Title: Synthesis of MUC1 glycopeptide thioesters and ligation via direct aminolysis
Contributor(s): Wilkinson, Brendan  (author)orcid ; Chun, Candy K Y (author); Payne, Richard J (author)
Publication Date: 2011
DOI: 10.1002/bip.21471
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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.
Publication Type: Journal Article
Source of Publication: Biopolymers, 96(2), p. 137-146
Publisher: John Wiley & Sons Inc
Place of Publication: United States of America
ISSN: 0006-3525
Field of Research (FOR): 030503 Organic Chemical Synthesis
030406 Proteins and Peptides
Socio-Economic Outcome Codes: 970103 Expanding Knowledge in the Chemical Sciences
929999 Health not elsewhere classified
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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