Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands
Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands
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DOI：
10.1016/j.steroids.2007.12.002
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发表时间：
2008-10-01
期刊：
影响因子：
2.7
通讯作者：
Buttgereit, Frank
中科院分区：
文献类型：
--
作者：
Lowenberg, Mark;Stahn, Cindy;Buttgereit, Frank
糖皮质激素（GC）是有效的抗炎和免疫抑制剂。不幸的是，它们也产生严重的副作用，限制了它们的使用。这种差异是深入寻找与传统GC相比具有更好的获益-风险比的新型GC受体配体的驱动力。更好地了解GC作用的分子模式可能会导致新的药物靶点的识别。基因组GC效应由反式阻遏或反式激活介导，后者主要负责GC副作用。我们在这里讨论新的GC受体配体，如选择性糖皮质激素受体激动剂（SEGRA），这可能会优化基因组GC的影响，因为它们优先诱导反式阻遏很少或没有反式激活活性。除了基因组GC的影响，GC也产生快速的基因组独立的活动，称为非基因组，我们在这里审查的可能影响，最近报道的非基因组GC诱导的免疫抑制T细胞的机制。研究表明，合成的GC地塞米松靶向膜结合的GC受体，导致T细胞受体信号传导受损。因此，膜连接GC受体可能是GC治疗的潜在候选靶点。最终目标是将这些分子见解转化为具有改善的治疗指数的新GC受体调节剂。(c)2007年爱思唯尔公司版权所有© 2016
Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant agents. Unfortunately, they also produce serious side effects that limit their usage. This discrepancy is the driving force for the intensive search for novel GC receptor ligands with a better benefit-risk ratio as compared to conventional GCs. A better understanding of the molecular mode of GC action might result in the identification of novel drug targets. Genomic GC effects are mediated by transrepression or trans activation, the latter being largely responsible for GC side effects. We here discuss novel GC receptor ligands, such as selective glucocorticoid receptor agonists (SEGRAs), which might optimize genomic GC effects as they preferentially induce transrepression with little or no transactivating activity. In addition to genomic GC effects, GCs also produce rapid genomic-independent activities, termed nongenomic, and we here review the possible implications of a recently reported mechanism underlying nongenomic GC-induced immunosuppression in T cells. It was shown that the synthetic GC dexamethasone targets membrane-bound GC receptors leading to impaired T cell receptor signaling. As a consequence, membrane-linked GC receptors might be a potential candidate target for GC therapy. The ultimate goal is to convert these molecular insights into new GC receptor modulators with an improved therapeutic index. (c) 2007 Elsevier Inc. All rights reserved,