Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule Library
Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule Library
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通过小分子文库的表型高通量筛选鉴定髓磷脂反应性 T 细胞的药物抑制剂
DOI：
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发表时间：
2007
影响因子：
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通讯作者：
H. Waldner
中科院分区：
文献类型：
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作者：
C. Rossi;D. Padmanaban;Jake Ni;L. Yeh;M. Glicksman;H. Waldner
对CNS的髓鞘蛋白组分具有反应性的炎性T细胞在多发性硬化（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）的发病机制中起关键作用。作者先前已经产生了主要携带T细胞受体（TCR）转基因的小鼠，该T细胞受体对髓鞘蛋白脂质蛋白（PLP）139-151具有特异性，并且自发地发展MS样瘫痪。来自健康转基因小鼠的T细胞以高度特异性的方式通过增殖和分泌促炎细胞因子如白细胞介素（IL）-2和IFN-γ对PLP 139 -151的刺激作出应答。为了鉴定可抑制炎性T细胞应答的药物样化合物，作者开发了一种使用来自PLP TCR转基因小鼠的原代T细胞的高通量筛选测定。他们筛选了41，184种遵循Lipinski规则的小分子化合物，用于抑制PLP反应性T细胞中促炎细胞因子的增殖和分泌。为此，筛选鉴定了6种分子量<500的无毒化合物，其以浓度依赖性方式抑制PLP反应性T细胞中的炎症反应。鉴定的化合物代表有效的线索，可以开发成新的治疗MS，可以口服给药。（Journal of Biomolecular Screening 2007：481-489）
Inflammatory T cells that are reactive to myelin protein components of the CNS play a critical role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The authors have previously generated mice that predominantly harbor T cells transgenic for a T-cell receptor (TCR) that is specific to the myelin proteolipid protein (PLP) 139-151 and that spontaneously develop MS-like paralysis. T cells from healthy transgenic mice respond to stimulation with PLP139-151 in a highly specific manner by proliferation and secretion of proinflammatory cytokines such as interleukin (IL)—2 and interferon (INF)—γ in vitro. To identify druglike compounds that may inhibit inflammatory T-cell responses, the authors have developed a high-throughput screening assay with primary T cells from PLP TCR transgenic mice. They have screened 41,184 small-molecule compounds that follow Lipinski's rules for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells. To this end, the screen identified 6 nontoxic compounds with a molecular weight <500 that inhibited inflammatory responses in PLP-reactive T cells in a concentration-dependent fashion. The identified compounds represent valid leads that may be developed into novel therapeutics for MS that could be administered orally. (Journal of Biomolecular Screening 2007:481-489)
影响因子：
4.4
作者：
L. Bradley;D. Dalton;M. Croft
通讯作者：
L. Bradley;D. Dalton;M. Croft
影响因子：
56.9
作者：
CANTRELL, DA;SMITH, KA
通讯作者：
SMITH, KA
影响因子：
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作者：
Liu, YC;Lashuel, HA;Lansbury, PT
通讯作者：
Lansbury, PT