Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition

Janice M. H. Cheng, Ligong Liu, Daniel G. Pellicci, Scott J. J. Reddiex, Rachel N. Cotton, Tan-Yun Cheng, David C. Young, Ildiko Van Rhijn, D. Branch Moody, Jamie Rossjohn, David P. Fairlie, Dale I. Godfrey, Spencer J. Williams

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1694-1701
Number of pages8
JournalChemistry - A European Journal
Volume23
Issue number7
DOIs
Publication statusPublished - 31 Jan 2017

Keywords

  • antigens
  • immunology
  • natural products
  • peptidolipids
  • T cells

Cite this

Cheng, Janice M. H. ; Liu, Ligong ; Pellicci, Daniel G. ; Reddiex, Scott J. J. ; Cotton, Rachel N. ; Cheng, Tan-Yun ; Young, David C. ; Van Rhijn, Ildiko ; Moody, D. Branch ; Rossjohn, Jamie ; Fairlie, David P. ; Godfrey, Dale I. ; Williams, Spencer J. / Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers : Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition. In: Chemistry - A European Journal. 2017 ; Vol. 23, No. 7. pp. 1694-1701.
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title = "Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition",
abstract = "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.",
keywords = "antigens, immunology, natural products, peptidolipids, T cells",
author = "Cheng, {Janice M. H.} and Ligong Liu and Pellicci, {Daniel G.} and Reddiex, {Scott J. J.} and Cotton, {Rachel N.} and Tan-Yun Cheng and Young, {David C.} and {Van Rhijn}, Ildiko and Moody, {D. Branch} and Jamie Rossjohn and Fairlie, {David P.} and Godfrey, {Dale I.} and Williams, {Spencer J.}",
year = "2017",
month = "1",
day = "31",
doi = "10.1002/chem.201605287",
language = "English",
volume = "23",
pages = "1694--1701",
journal = "Chemistry - A European Journal",
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Cheng, JMH, Liu, L, Pellicci, DG, Reddiex, SJJ, Cotton, RN, Cheng, T-Y, Young, DC, Van Rhijn, I, Moody, DB, Rossjohn, J, Fairlie, DP, Godfrey, DI & Williams, SJ 2017, 'Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition' Chemistry - A European Journal, vol. 23, no. 7, pp. 1694-1701. https://doi.org/10.1002/chem.201605287

Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers : Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition. / Cheng, Janice M. H.; Liu, Ligong; Pellicci, Daniel G.; Reddiex, Scott J. J.; Cotton, Rachel N.; Cheng, Tan-Yun; Young, David C.; Van Rhijn, Ildiko; Moody, D. Branch; Rossjohn, Jamie; Fairlie, David P.; Godfrey, Dale I.; Williams, Spencer J.

In: Chemistry - A European Journal, Vol. 23, No. 7, 31.01.2017, p. 1694-1701.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Total synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers

T2 - Diverse CD1a-restricted T cells display a common hierarchy of Lipopeptide recognition

AU - Cheng, Janice M. H.

AU - Liu, Ligong

AU - Pellicci, Daniel G.

AU - Reddiex, Scott J. J.

AU - Cotton, Rachel N.

AU - Cheng, Tan-Yun

AU - Young, David C.

AU - Van Rhijn, Ildiko

AU - Moody, D. Branch

AU - Rossjohn, Jamie

AU - Fairlie, David P.

AU - Godfrey, Dale I.

AU - Williams, Spencer J.

PY - 2017/1/31

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AB - 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.

KW - antigens

KW - immunology

KW - natural products

KW - peptidolipids

KW - T cells

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