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

4 Citations (Scopus)

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

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