首页> 外文期刊>Chemistry: A European journal >Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin- 838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition
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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

机译:结核分枝杆菌的总合成二脱氧卵黄脱离蛋白-838和立体异构体:不同的CD1A限制T细胞显示脂肽识别的常见等级

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摘要

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.
机译:结核分枝杆菌产生的二脱氧卵黄酰桶-838(DDM-838),一种脂肽,其在结合MHC样抗原呈递分子CD1a时效果地激活T细胞。结核病在仅痕量的量和先前的固相合成中产生DDM-838提供了亚毫克数量。我们描述了DDM-838的高产溶液相合成,其特征在于Mitsunobu替代,其避免在酯化期间赖氨酸的含量限制差异,以及防止Z-C20:1酰基链的双键异构化的酰胺化条件,以及为天然DDM-838提供具有等同抗原性的材料。在中央赖氨酸的立体化学中变化的DDM-838的异构体和C20:1酰基链的能力与CD1a限制的T细胞受体(TCR)识别。这些TCR来自无关的人类供体,对DDM-838异构体的面板表示相似的反应性,突出了脂肽反应性T细胞对天然DDM立体化学的精致敏感性。

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  • 来源
    《Chemistry: A European journal》 |2017年第7期|共8页
  • 作者单位

    School of Chemistry and Bio21 Molecular Science and Biotechnology Institute University of Melbourne Parkville Victoria 3010 (Australia);

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland Brisbane Queensland 4072 (Australia);

    Department of Microbiology and Immunology Peter Doherty Institute for Infection and Immunity University of Melbourne Parkville Victoria 3010 (Australia);

    Department of Microbiology and Immunology Peter Doherty Institute for Infection and Immunity University of Melbourne Parkville Victoria 3010 (Australia);

    Division of Rheumatology Immunology and Allergy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 (USA);

    Division of Rheumatology Immunology and Allergy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 (USA);

    Division of Rheumatology Immunology and Allergy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 (USA);

    Division of Rheumatology Immunology and Allergy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 (USA);

    Division of Rheumatology Immunology and Allergy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 (USA);

    Infection and Immunity Program Department of Biochemistry and Molecular Biology Biomedicine Discovery Institute Monash University Clayton VIC 3800 (Australia);

    Division of Chemistry and Structural Biology Institute for Molecular Bioscience The University of Queensland Brisbane Queensland 4072 (Australia);

    Department of Microbiology and Immunology Peter Doherty Institute for Infection and Immunity University of Melbourne Parkville Victoria 3010 (Australia);

    School of Chemistry and Bio21 Molecular Science and Biotechnology Institute University of Melbourne Parkville Victoria 3010 (Australia);

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 应用化学;
  • 关键词

    antigens; immunology; natural products; peptidolipids; T cells;

    机译:抗原;免疫学;天然产品;肽脂;T细胞;

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