Lipid length and iso-branching of trehalose diesters influences Mincle agonist activity

Khan, Ayesha; Kodar, Kristel; Timmer, Mattie S. M.; Stocker, Bridget L.

doi:10.1016/j.tet.2017.11.076

Cited by 28 publications

(39 citation statements)

References 46 publications

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“…From this work, it was determined that a lipid length of >C12 was required to activate macrophages, with the greatest amount of IL-6, IL-1β, and NO being produced by the C22 ( 7h ) and C26 ( 7i ) TDEs. In subsequent studies, we confirmed that this immune response was Mincle-dependent, and also demonstrated that the C12-TDE ( 7d ) elicited the production of MIP-2 by BMMs, but not other pro-inflammatory cytokines (IL-1β, IL-6, IL-12), thereby providing the first example of a TDE with a chain length of ≤ C12 leading to a Mincle-dependent immune response and one that is less inflammatory in nature ( 48 ). In related studies, Kallerup et al demonstrated that the incorporation of the C16 ( 7e ) and C18 ( 7f ) TDEs into DDA liposomes led to a similar in vivo immunological response to that elicited by TDB ( 7h )/DDA liposomes ( 65 ).…”

Section: Trehalose Diesters (Tdes)supporting

confidence: 68%

“…For example, studies with TDMs revealed slight differences in the ability of TDMs with different mycolic acids to activate BMDCs in vitro , whereby it was demonstrated that increased polarity in the middle of the meromycolate branch does not increase Mincle agonist activity ( 27 ). Similarly, iso-TDEs (maradolipids) led to greater cytokine production by BMMs in vitro compared to their linear counterparts ( 48 ). The ability of Mincle to differentiate between isomers has also been demonstrated in studies with optically pure CMA esters of R - and S -glycerol, whereby the S -isomers was better able to activate reporter cell lines expressing hMincle ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Various TDCMs and dehydroxy derivatives have been synthesized, as have the maradolipids, which have been first isolated from the dauer larva stage of Caenorhabditis elegans . Of these branched TDEs, TDCM ( 1 ) and maradolipids ( 6a–f ) have been confirmed to be macrophage inducible C-type lectin agonists ( 42 , 43 , 47 , 48 ).…”

Section: Trehalose Diesters (Tdes)mentioning

confidence: 99%

“…Iso-branched TDEs, also known as maradolipids, were first isolated in 2010 from the dauer larva stage of Caenorhabditis elegans ( 51 ) and synthesized shortly thereafter ( 52 – 54 ). Our group recently determined that maradolipids ( 6a–f , Figure 3 ) are Mincle-ligands ( 48 ). On the whole, the iso-branched maradolipids led to greater cytokine production (IL-6, IL-1β, IL-12, IL-12, MIP-2 by BMMs), and a faster immune response when compared to their linear counterparts.…”

Section: Trehalose Diesters (Tdes)mentioning

confidence: 99%

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Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

et al. 2018

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The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor able to recognize both damage-associated and pathogen-associated molecular patterns, and in this respect, there has been much interest in determining the scope of ligands that bind Mincle and how structural modifications to these ligands influence ensuing immune responses. In this review, we will present Mincle ligands of known chemical structure, with a focus on ligands that have been synthetically prepared, such as trehalose glycolipids, glycerol-based ligands, and 6-acylated glucose and mannose derivatives. The ability of the different classes of ligands to influence the innate, and consequently, the adaptive, immune response will be described, and where appropriate, structure–activity relationships within each class of Mincle ligands will be presented.

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Section: Trehalose Diesters (Tdes)supporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Trehalose Diesters (Tdes)mentioning

confidence: 99%

Section: Trehalose Diesters (Tdes)mentioning

confidence: 99%

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Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

et al. 2018

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“…Thus, our findings further illustrate species‐specific differences that may exist with regard to Mincle expression 17,46 . Lastly, as functional changes to Mincle agonists can further enhance the type 1 helper immune response, 17,47,48 this highlights the potential of developing additional Mincle agonists as anticancer adjuvants.…”

Section: Discussionsupporting

confidence: 53%

The coadministration of trehalose dibehenate and monosodium urate crystals promotes an antitumor phenotype in human‐derived myeloid cells

et al. 2020

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Trehalose dibehenate (TDB), a ligand for the macrophage-inducible C-type lectin, has shown promise as an adjuvant for preventative vaccines and also as an anticancer agent in murine assays. The potential for TDB to affect the antitumor immune response of human myeloid cells, however, has not been studied. We investigated the effect of the adjuvants TDB and monosodium urate (MSU) crystals on the protumor or antitumor immune phenotype of human monocytes, macrophages and monocyte-derived dendritic cells (Mo-DCs). TDB treatment alone led to an inflammatory response in all three cell types, which was most pronounced when using human monocytes, with MSU augmenting this response. TDB also decreased cell surface markers associated with a protumorigenic phenotype, with MSU showing some ability to augment this response. Notably, a significant reduction in CD115 was observed for all antigen-presenting cells upon TDB or MSU + TDB treatment. The potential to increase the antigen-presenting capabilities of the myeloid cells was also observed upon treatment with TDB and MSU + TDB, as indicated by the upregulation of cell surface markers such as CD86 for all three cell types and a favorable ratio of interleukin (IL)-12p40 to IL-10 for monocytes stimulated with MSU + TDB. There was no significant production of IL-12p40 by Mo-DC; however, in a mixed lymphocyte assay, MSU + TDB costimulation of Mo-DC led to a significant increase in CD4 + T-cell numbers and in the IL-12p40-to-IL-10 ratio. Taken together, these findings show for the first time the potential of MSU + TDB costimulation to favor a tumor-suppressive phenotype in human-derived myeloid cells.

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Synthesis of 6,6′‐Bis(O‐4‐arylethynylbenzoyl)‐α,α‐Trehaloses and Their Utilization as Fluorescent Probes for Cellular Imaging

et al. 2018

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A series of 6,6′‐bis(O‐4‐arylethynylbenzoyl)‐α,α‐trehaloses (aryl groups; 1a: 1‐pyrenyl, 1b: 9‐anthryl, 1c: phenyl) were synthesized and fully characterized. Their photophysical properties were investigated by UV/Vis/fluorescence spectroscopy, and were rationalized by TDDFT calculations. Moreover, the emission maxima of 1a and 1b in THF/H2O considerably shifted to a longer wavelength region with increasing H2O fraction owing to the formation of excimers. The pyrenyl derivative 1a was efficiently taken into HeLa CD4+ human cervical cancer cells and emitted bright green fluorescence.

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Lipid length and iso-branching of trehalose diesters influences Mincle agonist activity

Cited by 28 publications

References 46 publications

Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

The coadministration of trehalose dibehenate and monosodium urate crystals promotes an antitumor phenotype in human‐derived myeloid cells

Synthesis of 6,6′‐Bis(O‐4‐arylethynylbenzoyl)‐α,α‐Trehaloses and Their Utilization as Fluorescent Probes for Cellular Imaging

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