Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants
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- Amy J. Foster
- School of Chemical and Physical Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
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- Masahiro Nagata
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
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- Xiuyuan Lu
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
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- Amy T. Lynch
- School of Chemical and Physical Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
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- Zakaria Omahdi
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
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- Eri Ishikawa
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
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- Sho Yamasaki
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
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- Mattie S. M. Timmer
- School of Chemical and Physical Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
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- Bridget L. Stocker
- School of Chemical and Physical Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
書誌事項
- 公開日
- 2018-01-18
- 資源種別
- journal article
- DOI
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- 10.1021/acs.jmedchem.7b01468
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
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.
収録刊行物
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- Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry 61 (3), 1045-1060, 2018-01-18
American Chemical Society (ACS)
