Journal article

Total Synthesis of Mycobacterium tuberculosis Dideoxymy-cobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition

Janice MH Cheng, Ligong Liu, Daniel G Pellicci, Scott JJ 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

CHEMISTRY-A EUROPEAN JOURNAL | WILEY-V C H VERLAG GMBH | Published : 2017

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..

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Grants

Awarded by Australian Research Council


Awarded by NHMRC ECF fellowship


Awarded by NHMRC Senior Principal Research Fellowships


Awarded by NIH


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Funding Acknowledgements

This work was supported by the Australian Research Council (DP130102763, DP160100597, FT130100103, CE140100011 and LE110100106). DGP is supported by an NHMRC ECF fellowship (1054431); D.P.F.and D.I.G.are supported by NHMRC Senior Principal Research Fellowships (1027369, 1020770); J.R.is supported by an ARC Laureate Fellowship; D.B.M.is supported by the Bill and Melinda Gates Foundation Vaccine Accelerator Award and NIH (R01 AI1049313 and U19 AI111224).