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6-C-Linked trehalose glycolipids signal through Mincle and exhibit potent adjuvant activity.
Thathsaranie P Manthrirathna, M A; Kodar, Kristel; Ishizuka, Shigenari; Dangerfield, Emma M; Xiuyuan, Lu; Yamasaki, Sho; Stocker, Bridget L; S M Timmer, Mattie.
Afiliación
  • Thathsaranie P Manthrirathna MA; School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
  • Kodar K; School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
  • Ishizuka S; Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
  • Dangerfield EM; School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
  • Xiuyuan L; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
  • Yamasaki S; Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Division of Molecular Immunology, Medical Institute of Bioregulation,
  • Stocker BL; School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
  • S M Timmer M; School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand; Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
Bioorg Chem ; 133: 106345, 2023 04.
Article en En | MEDLINE | ID: mdl-36764230
Many studies have investigated the Mincle-mediated agonist activity of α,α'-trehalose-6,6́-glycolipids, however, none have considered how the position, or absence, of the ester moiety influences Mincle-mediated agonist activity. We prepared a variety of 6-C-linked α,α'-trehalose glycolipids containing inverted esters, ketone, carboxy or no carbonyl moieties. Modelling studies indicated that these derivatives bind to the CRD of Mincle in a manner similar to that of the prototypical Mincle agonist, trehalose dibehenate (TDB), with NFAT-GFP reporter cell assays confirming that all compounds, apart from derivatives with short alkyl chains, led to robust Mincle signalling. It was also observed that a carbonyl moiety was needed for good Mincle-mediated signalling. The ability of the compounds to induce mIL-1 ß and mIL-6 production by bone marrow-derived macrophages (BMDMs) further demonstrated the agonist activity of the compounds, with the presence of a carbonyl moiety and longer lipid chains augmenting cytokine production. Notably, a C20 inverted ester led to levels of mIL-1ß that were significantly greater than those induced by TDB. The same C20 inverted ester also led to a significant increase in hIL-1ß and hIL-6 by human monocytes, and exhibited no toxicity, as demonstrated using BMDMs in an in vitro Sytox Green assay. The ability of the inverted ester to enhance antigen-mediated immune responses was then determined. In these studies, the inverted ester was found to augment the OVA-specific Th1/Th7 immune response in vitro, and exhibit adjuvanticity that was better than that of TDB in vivo, as evidenced by a significant increase in IgG antibodies for the inverted ester but not TDB when using OVA as a model antigen.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trehalosa / Glucolípidos Límite: Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trehalosa / Glucolípidos Límite: Humans Idioma: En Revista: Bioorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos