Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants

Amy J. Foster, Masahiro Nagata, Xiuyuan Lu, Amy T. Lynch, Zakaria Omahdi, Eri Ishikawa, Sho Yamasaki, Mattie S.M. Timmer, Bridget L. Stocker

    Research output: Contribution to journalArticlepeer-review

    35 Citations (Scopus)


    Effective Th1-stimulating vaccine adjuvants typically activate antigen presenting cells (APCs) through pattern recognition receptors (PRRs). Macrophage inducible C-type lectin (Mincle) is a PRR expressed on APCs and has been identified as a target for Th1-stimulating adjuvants. Herein, we report on the synthesis and adjuvanticity of rationally designed brartemicin analogues containing long-chain lipids and demonstrate that they are potent Mincle agonists that activate APCs to produce inflammatory cytokines in a Mincle-dependent fashion. Mincle binding, however, does not directly correlate to a functional immune response. Mutation studies indicated that the aromatic residue of lead compound 9a has an important interaction with Mincle Arg183. In vivo assessment of 9a highlighted the capability of this analogue to augment the Th1 response to a model vaccine antigen. Taken together, our results show that lipophilic brartemicin analogues are potent Mincle agonists and that 9a has superior in vivo adjuvant activity compared to TDB.

    Original languageEnglish
    Pages (from-to)1045-1060
    Number of pages16
    JournalJournal of Medicinal Chemistry
    Issue number3
    Publication statusPublished - Feb 8 2018

    All Science Journal Classification (ASJC) codes

    • Molecular Medicine
    • Drug Discovery


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