PMID- 36764230
OWN - NLM
STAT- MEDLINE
DCOM- 20230320
LR  - 20230320
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 133
DP  - 2023 Apr
TI  - 6-C-Linked trehalose glycolipids signal through Mincle and exhibit potent 
      adjuvant activity.
PG  - 106345
LID - S0045-2068(23)00005-6 [pii]
LID - 10.1016/j.bioorg.2023.106345 [doi]
AB  - Many studies have investigated the Mincle-mediated agonist activity of 
      alpha,alpha'-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 alpha,alpha'-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 beta 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-1beta that 
      were significantly greater than those induced by TDB. The same C20 inverted ester 
      also led to a significant increase in hIL-1beta 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.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Thathsaranie P Manthrirathna, M A
AU  - Thathsaranie P Manthrirathna MA
AD  - School of Chemical and Physical Sciences, Victoria University of Wellington, PO 
      Box 600, Wellington, New Zealand.
FAU - Kodar, Kristel
AU  - Kodar K
AD  - 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.
FAU - Ishizuka, Shigenari
AU  - Ishizuka S
AD  - 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.
FAU - Dangerfield, Emma M
AU  - Dangerfield EM
AD  - 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.
FAU - Xiuyuan, Lu
AU  - Xiuyuan L
AD  - Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka 
      University, Suita, Osaka, Japan.
FAU - Yamasaki, Sho
AU  - Yamasaki S
AD  - 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, Kyushu 
      University, Fukuoka, Fukuoka, Japan; Division of Molecular Immunology, Medical 
      Mycology Research Center, Chiba University, Chiba, Japan.
FAU - Stocker, Bridget L
AU  - Stocker BL
AD  - 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.
FAU - S M Timmer, Mattie
AU  - S M Timmer M
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230111
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Glycolipids)
RN  - B8WCK70T7I (Trehalose)
RN  - 0 (Adjuvants, Immunologic)
SB  - IM
MH  - Humans
MH  - *Glycolipids/pharmacology
MH  - *Trehalose/pharmacology/metabolism
MH  - Adjuvants, Immunologic/pharmacology
MH  - Macrophages/metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - Adjuvant
OT  - Glycolipid
OT  - Immune response
OT  - Macrophage
OT  - Mincle
OT  - Synthesis
OT  - Trehalose glycolipids
OT  - Vaccine
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/02/11 06:00
MHDA- 2023/03/21 06:00
CRDT- 2023/02/10 18:19
PHST- 2022/11/15 00:00 [received]
PHST- 2022/12/19 00:00 [revised]
PHST- 2023/01/04 00:00 [accepted]
PHST- 2023/02/11 06:00 [pubmed]
PHST- 2023/03/21 06:00 [medline]
PHST- 2023/02/10 18:19 [entrez]
AID - S0045-2068(23)00005-6 [pii]
AID - 10.1016/j.bioorg.2023.106345 [doi]
PST - ppublish
SO  - Bioorg Chem. 2023 Apr;133:106345. doi: 10.1016/j.bioorg.2023.106345. Epub 2023 
      Jan 11.