Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis.
Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis.
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DOI：
10.1155/2012/389404
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发表时间：
2012
影响因子：
2
通讯作者：
Fitzpatrick LR
中科院分区：
文献类型：
--
作者：
Fitzpatrick LR
本综述确定了 IL-23/IL-17 轴内炎症性肠病 (IBD) 的可能药理学靶点。具体来说，IL-23/IL-17 途径中有几个靶标可用于抗体或小分子抑制剂的潜在药理干预。这些靶标包括 TL1A（肿瘤坏死因子样分子）、DR3（死亡受体 3）、IL-23、IL-17 以及 IL-23 和 IL-17 的受体。与 IBD 相关，还有其他新的药理学靶点。这些目标包括抑制特定的免疫蛋白酶体亚基、阻断鞘脂代谢中的关键酶（鞘氨醇激酶）以及调节 NF-κB/STAT3 相互作用。对于 IL-23 和 IL-17 途径中关键成分的药理学抑制，存在几种好的方法。这些方法包括针对 TL1A、IL-17 受体、Fc 融合蛋白的特异性单克隆抗体、针对 IL-17F 的特异性抗体以及 IL-17 的小分子抑制剂（如维多氟地莫）。此外，IBD 靶向药物开发的其他潜在方法包括 SK 的特异性化学抑制剂、针对免疫蛋白酶体催化亚基的特异性小分子抑制剂以及 STAT3 和 NF-κB 信号转导系统的双重抑制剂。未来，仍需要精心设计的临床前研究来确定哪些药理学方法将为进入临床试验提供最佳疗效和安全性的药物。
This review identifies possible pharmacological targets for inflammatory bowel disease (IBD) within the IL-23/IL-17 axis. Specifically, there are several targets within the IL-23/IL-17 pathways for potential pharmacological intervention with antibodies or small molecule inhibitors. These targets include TL1A (tumor necrosis factor-like molecule), DR3 (death receptor 3), IL-23, IL-17 and the receptors for IL-23 and IL-17. As related to IBD, there are also other novel pharmacological targets. These targets include inhibiting specific immunoproteasome subunits, blocking a key enzyme in sphingolipid metabolism (sphingosine kinase), and modulating NF-κB/STAT3 interactions. Several good approaches exist for pharmacological inhibition of key components in the IL-23 and IL-17 pathways. These approaches include specific monoclonal antibodies to TL1A, IL-17 receptor, Fc fusion proteins, specific antibodies to IL-17F, and small molecule inhibitors of IL-17 like Vidofludimus. Also, other potential approaches for targeted drug development in IBD include specific chemical inhibitors of SK, specific small molecule inhibitors directed against catalytic subunits of the immunoproteasome, and dual inhibitors of the STAT3 and NF-κB signal transduction systems. In the future, well-designed preclinical studies are still needed to determine which of these pharmacological approaches will provide drugs with the best efficacy and safety profiles for entrance into clinical trials.