Chemical Modulators of Mucosal Associated Invariant T Cells.
Chemical Modulators of Mucosal Associated Invariant T Cells.
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DOI：
10.1021/acs.accounts.1c00359
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发表时间：
2021-09-07
影响因子：
18.3
通讯作者：
Fairlie DP
中科院分区：
文献类型：
--
作者：
Mak JYW;Liu L;Fairlie DP
在过去的十年中，我们为微生物天然产物和合成配体的化学做出了贡献，这些配体与核黄素和尿嘧啶有关，可调节称为粘膜相关不变T细胞（MAIT细胞）的免疫细胞。这些高度丰富的T淋巴细胞直到2003年才被发现，并因其在哺乳动物免疫学中的重要性而得到认可。与其他T细胞不同，MAIT细胞不被肽或脂质抗原激活。在与免疫学和结构生物学研究小组的合作中，我们发现它们反而被细菌合成的不稳定的含氮杂环激活。最有效的天然存在的活化化合物（抗原）是5-（2-氧代亚丙基氨基）-D-核糖基氨基尿嘧啶（5-OP-RU）。这种化合物是一种亚胺（席夫碱），通过核黄素（维生素B2）生物合成的中间体与哺乳动物和微生物糖酵解的代谢副产物之间的缩合形成。尽管由于分子内环闭合或水解，它在水中非常不稳定，但我们能够开发出一种非酶促合成，在非水溶剂中产生纯的动力学稳定的化合物。该化合物由于其MAIT细胞的有效活化（EC 50 = 2 pM）及其开发成用于检测和表征组织中MAIT细胞的免疫试剂而彻底改变了MAIT细胞免疫学的研究。MAIT细胞现在与关键的生理过程和疾病有关，包括抗菌防御，组织修复，移植物抗宿主病，胃炎，炎症性肠病和癌症的调节。5-OP-RU激活MAIT细胞，并且像疫苗一样，已被证明可以保护小鼠免受细菌感染和癌症。关于5-OP-RU与其双重蛋白靶点（主要组织相容性复合物I类相关蛋白（MR 1）和MAIT细胞受体（MAIT TCR））结合的机制研究涉及合成化学、2D 1H NMR光谱、质谱、计算机建模和分子动力学模拟、生物化学、细胞和免疫学测定以及蛋白质结构生物学。这些联合研究揭示了溶液中5-OP-RU对蛋白结合和抗原呈递和效价的结构影响;为开发强效（EC 50 = 2 nM）和水稳定的类似物提供了信息;导致荧光类似物用于检测和跟踪细胞内和细胞上的结合蛋白;并发现了结合MR 1并调节MAIT细胞功能的药物和药物样分子。MAIT细胞为化学合成提供了新的机会，以增强MR 1或MAIT TCR蛋白的小分子配体的稳定性、效力、选择性和生物利用度，并有助于理解T细胞免疫和开发有前景的新型免疫调节药物。
Over the past decade, we have contributed to the chemistry of microbial natural products and synthetic ligands, related to riboflavin and uracils, that modulate immune cells called mucosal associated invariant T cells (MAIT cells). These highly abundant T lymphocytes were only discovered in 2003 and have become recognized for their importance in mammalian immunology. Unlike other T cells, MAIT cells are not activated by peptide or lipid antigens. In collaboration with immunology and structural biology research groups, we discovered that they are instead activated by unstable nitrogen-containing heterocycles synthesized by bacteria. The most potent naturally occurring activating compound (antigen) is 5-(2-oxopropylideneamino)-D-ribitylaminouracil (5-OP-RU). This compound is an imine (Schiff base) formed through condensation between an intermediate in the biosynthesis of riboflavin (vitamin B2) and a metabolic byproduct of mammalian and microbial glycolysis. Although it is very unstable in water due to intramolecular ring closure or hydrolysis, we were able to develop a non-enzymatic synthesis that yields a pure kinetically stable compound in a nonaqueous solvent. This compound has revolutionized the study of MAIT cell immunology due to its potent activation (EC50 = 2 pM) of MAIT cells and its development into immunological reagents for detecting and characterizing MAIT cells in tissues. MAIT cells are now linked to key physiological processes and disease, including antibacterial defense, tissue repair, regulation of graft-vs-host disease, gastritis, inflammatory bowel diseases, and cancer. 5-OP-RU activates MAIT cells and, like a vaccine, has been shown to protect mice from bacterial infections and cancers. Mechanistic studies on the binding of 5-OP-RU to its dual protein targets, the major histocompatibility complex class I related protein (MR1) and the MAIT cell receptor (MAIT TCR), have involved synthetic chemistry, 2D 1H NMR spectroscopy, mass spectrometry, computer modeling and molecular dynamics simulations, biochemical, cellular, and immunological assays, and protein structural biology. These combined studies have revealed structural influences for 5-OP-RU in solution on protein binding and antigen presentation and potency; informed the development of potent (EC50 = 2 nM) and water stable analogues; led to fluorescent analogues for detecting and tracking binding proteins in and on cells; and enabled discovery of drugs and drug-like molecules that bind MR1 and modulate MAIT cell function. MAIT cells offer new opportunities for chemical synthesis to enhance the stability, potency, selectivity, and bioavailability of small molecule ligands for MR1 or MAIT TCR proteins, and to contribute to the understanding of T cell immunity and the development of prospective new immunomodulating medicines.
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影响因子：
5.8
作者：
Leeansyah E;Hey YY;Sia WR;Ng JHJ;Gulam MY;Boulouis C;Zhu F;Ahn M;Mak JYW;Fairlie DP;Kwa ALH;Sandberg JK;Wang LF
通讯作者：
Wang LF
影响因子：
30.5
作者：
Awad, Wael;Ler, Geraldine J. M.;Rossjohn, Jamie
通讯作者：
Rossjohn, Jamie
DOI：
10.1126/science.aax6624
发表时间：
2019-10-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Constantinides MG;Link VM;Tamoutounour S;Wong AC;Perez-Chaparro PJ;Han SJ;Chen YE;Li K;Farhat S;Weckel A;Krishnamurthy SR;Vujkovic-Cvijin I;Linehan JL;Bouladoux N;Merrill ED;Roy S;Cua DJ;Adams EJ;Bhandoola A;Scharschmidt TC;Aubé J;Fischbach MA;Belkaid Y
通讯作者：
Belkaid Y
影响因子：
4.4
作者：
Howson, Lauren J.;Li, Jasmine;Rossjohn, Jamie
通讯作者：
Rossjohn, Jamie
影响因子：
9.8
作者：
Boulouis, Caroline;Sia, Wan Rong;Leeansyah, Edwin
通讯作者：
Leeansyah, Edwin