Chemobacterial Synthesis of a Sialyl‐Tn Cyclopeptide Vaccine Candidate. (17th July 2017)

• Record Type: Journal Article
• Authors: Richard, Emeline; Pifferi, Carlo; Fiore, Michele; Samain, Eric; Le Gouëllec, Audrey; Fort, Sébastien; Renaudet, Olivier; Priem, Bernard
• Is Part Of: Chembiochem. Volume 18:Number 17(2017)
• Page Start: 1730
• Page End: 1734
• Publication Date: 2017-07-17
• Subjects: antigens -- chemobacterial synthesis -- peptides -- sialyl–Tn -- vaccine conjugates; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700240
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: A conjugatable form of the tumour‐associated carbohydrate antigen sialyl‐Tn (Neu5Ac‐α‐2, 6‐GalNAc) was efficiently produced in Escherichia coli . Metabolically engineered E. coli strains overexpressing the 6‐sialyltransferase gene of Photobacterium sp. and CMP‐Neu5Ac synthetase genes of Neisseria meningitidis were cultivated at high density in the presence of GalNAc‐α‐propargyl as the exogenous acceptor. The target disaccharides, which were produced on the scale of several hundreds of milligrams, were then conjugated by using copper(I)‐catalysed azide–alkyne cycloaddition click chemistry to a fully synthetic and immunogenic scaffold with the aim to create a candidate anticancer vaccine. Four sialyl‐Tn epitopes were introduced on the upper face of an azido‐functionalised multivalent cyclopeptide scaffold, the lower face of which was previously modified by an immunogenic polypeptide, PADRE. The ability of the resulting glycoconjugate to interact with oncofoetal sialyl‐Tn monoclonal antibodies was confirmed in ELISA assays. Abstract : Call for immunity : A sialyl‐Tn (STn) cyclopeptide scaffold bearing the helper T‐cell peptide epitope (PADRE) is synthesised. Although the resulting glycoconjugate lacks the native MUC1 peptide sequence, its ability to interact with sialyl‐Tn monoclonal antibodies is confirmed in ELISA assays. The availability of sialylated carbohydrate antigens opens up possibilities for the development of a new generation of synthetic antitumour vaccines.