ChemBioChem
ChemBioChem
5 years ago

Chemobacterial Synthesis of a Sialyl-Tn Cyclopeptide Vaccine Candidate

Chemobacterial Synthesis of a Sialyl-Tn Cyclopeptide Vaccine Candidate
Sébastien Fort, Carlo Pifferi, Michele Fiore, Eric Samain, Bernard Priem, Audrey Le Gouëllec, Olivier Renaudet, Emeline Richard
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. 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cbic.201700240

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