Synthesis of a Self-Adjuvanting MUC1 Vaccine via Diselenide-Selenoester Ligation-Deselenization

Access to lipopeptide-based vaccines for immunological studies remains a significant challenge owing to the amphipathic nature of the molecules, which makes them difficult to synthesize and purify to homogeneity. Here, we describe the application of a new peptide ligation technology, the diselenide-...

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Bibliographic Details
Published in:ACS chemical biology 2018-12, Vol.13 (12), p.3279-3285
Main Authors: McDonald, David M, Hanna, Cameron C, Ashhurst, Anneliese S, Corcilius, Leo, Byrne, Scott N, Payne, Richard J
Format: Article
Language:English
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Summary:Access to lipopeptide-based vaccines for immunological studies remains a significant challenge owing to the amphipathic nature of the molecules, which makes them difficult to synthesize and purify to homogeneity. Here, we describe the application of a new peptide ligation technology, the diselenide-selenoester ligation (DSL), to access self-adjuvanting glycolipopeptide vaccines. We show that rapid ligation of glyco- and lipopeptides is possible via DSL in mixed organic solvent-aqueous buffer and, when coupled with deselenization chemistry, affords rapid and efficient access to a vaccine candidate possessing a MUC1 glycopeptide epitope and the lipopeptide adjuvant Pam2Cys. This construct was shown to elicit MUC1-specific antibody and cytotoxic T lymphocyte responses in the absence of any other injected lipids or adjuvants. The inclusion of the helper T cell epitope PADRE both boosted the antibody response and resulted in elevated cytokine production.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.8b00675