Asymmetric Total Synthesis and Structural Revision of DAT 2 , an Antigenic Glycolipid from Mycobacterium tuberculosis

DAT is a member of the diacyl trehalose family (DAT) of antigenic glycolipids located in the mycomembrane of Mycobacterium tuberculosis (Mtb). Recently it was shown that the molecular structure of DAT had been incorrectly assigned, but the correct structure remained elusive. Herein, the correct mole...

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Bibliographic Details
Published inAngewandte Chemie International Edition Vol. 63; no. 19; p. e202318582
Main Authors Lin, Zonghao, Kaniraj, Jeya Prathap, Holzheimer, Mira, Nigou, Jérôme, Gilleron, Martine, Hekelaar, Johan, Minnaard, Adriaan J
Format Journal Article
LanguageEnglish
Published Germany 06.05.2024
Subjects
stereochemistry
antigenicity
di-O-acyl trehalose
organic synthesis
structural revision
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Summary:DAT is a member of the diacyl trehalose family (DAT) of antigenic glycolipids located in the mycomembrane of Mycobacterium tuberculosis (Mtb). Recently it was shown that the molecular structure of DAT had been incorrectly assigned, but the correct structure remained elusive. Herein, the correct molecular structure of DAT and its methyl-branched acyl substituent mycolipanolic acid is determined. For this, four different stereoisomers of mycolipanolic acid were prepared in a stereoselective and unified manner, and incorporated into DAT . A rigorous comparison of the four isomers to the DAT isolated from Mtb H37Rv by NMR, HPLC, GC, and mass spectrometry allowed a structural revision of mycolipanolic acid and DAT . Activation of the macrophage inducible Ca -dependent lectin receptor (Mincle) with all four stereoisomers shows that the natural stereochemistry of mycolipanolic acid / DAT provides the strongest activation, which indicates its high antigenicity and potential application in serodiagnostics and vaccine adjuvants.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202318582