Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants
| Autor: | Mattie S. M. Timmer, Amy J. Foster, Shou Yamasaki, Amy T. Lynch, Xiuyuan Lu, Masahiro Nagata, Bridget L. Stocker, Eri Ishikawa, Zakaria Omahdi |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein Conformation medicine.medical_treatment Antigen-Presenting Cells Pharmacology 01 natural sciences Proinflammatory cytokine 03 medical and health sciences Mice Immune system Adjuvants Immunologic In vivo Adjuvanticity Drug Discovery medicine Macrophage Animals Lectins C-Type Receptors Immunologic Antigen-presenting cell Vaccines 010405 organic chemistry Chemistry Pattern recognition receptor Trehalose Th1 Cells 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Molecular Medicine Glycolipids Adjuvant |
| Zdroj: | Journal of medicinal chemistry. 61(3) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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