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Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin‐838 and Stereoisomers: Diverse CD1a‐Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition
Author(s) -
Cheng Janice M. H.,
Liu Ligong,
Pellicci Daniel G.,
Reddiex Scott J. J.,
Cotton Rachel N.,
Cheng TanYun,
Young David C.,
Van Rhijn Ildiko,
Moody D. Branch,
Rossjohn Jamie,
Fairlie David P.,
Godfrey Dale I.,
Williams Spencer J.
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605287
Subject(s) - lipopeptide , mycobacterium tuberculosis , antigenicity , stereochemistry , chemistry , yield (engineering) , antigen , biology , tuberculosis , materials science , bacteria , immunology , medicine , genetics , pathology , metallurgy
Mycobacterium tuberculosis produces dideoxymycobactin‐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.