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

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

DOI: 10.1002/chem.201605287

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..

View full abstract

University of Melbourne Researchers

Dale Godfrey Author Microbiology and Immunology

Daniel Pellicci Author Microbiology and Immunology

Spencer Williams Author Chemistry

Related Projects (6)

BREAKING IT DOWN: DISSECTING THE MECHANISM AND EXPLORING NEW INHIBITION STRATEGIES FOR POLYSACCHARIDE CLEAVING ENZYMES

Mannose, a common carbohydrate building block, is present in a wide variety of complex polysaccharides including energy storage polymers and..

Unravelling the immunology of complex glycolipids by chemical synthesis

This project seeks to develop new approaches to chemically synthesise bacterial and fungal glycolipids and develop a molecular-level underst..

AN ADVANCED FLOW CYTOMETRY FACILITY FOR THE PETER DOHERTY INSTITUTE

The establishment of a flow cytometry facility in the new Peter Doherty Institute for Infection and Immunity will enhance capacity to invest..

Defining the biosynthesis and immunological properties of complex bacterial glycolipids

We will study how sugar-lipids are made by industrially, agriculturally and medically important bacteria, and how they interact with the imm..

LIPID ANTIGEN RECOGNITION BY DIVERSE CD1-RESTRICTED T CELLS

Natural Killer T (NKT) cells are a specialized T cell lineage that form a key part of the adaptive immune response required for protection a..

RESEARCH FELLOWSHIP

Professor Godfrey is an immunologist with a long standing history as a pioneer in the study of a specialised type of white blood cell, known..

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).