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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

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. and Williams, Spencer J. 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 23 (7) , pp. 1694-1701. 10.1002/chem.201605287

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Antigens; Immunology; Natural products; Peptidolipids; T cells
Publisher: Wiley
ISSN: 0947-6539
Date of First Compliant Deposit: 16 July 2018
Date of Acceptance: 7 December 2016
Last Modified: 17 Jul 2018 04:37
URI: http://orca-mwe.cf.ac.uk/id/eprint/100002

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