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  ORCID: https://orcid.org/0000-0002-2020-7522, 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: | 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: | 18 Oct 2025 08:15 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/100002 |
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