期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 23, 期 7, 页码 1694-1701出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201605287
关键词
antigens; immunology; natural products; peptidolipids; T cells
资金
- Australian Research Council [DP130102763, DP160100597, FT130100103, CE140100011, LE110100106]
- NHMRC ECF fellowship [1054431]
- NHMRC Senior Principal Research Fellowships [1027369, 1020770]
- ARC Laureate Fellowship
- NIH [R01 AI1049313, U19 AI111224]
- Bill and Melinda Gates Foundation Vaccine Accelerator Award
- Australian Research Council [LE110100106] Funding Source: Australian Research Council
Mycobacterium tuberculosis produces dideoxymy-cobactin- 838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry.
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