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A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.bmc.2020.115327 Sukhvir Kaur 1 , Yogita Bansal 1 , Raj Kumar 2 , Gulshan Bansal 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-20 , DOI: 10.1016/j.bmc.2020.115327 Sukhvir Kaur 1 , Yogita Bansal 1 , Raj Kumar 2 , Gulshan Bansal 1
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Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine. Its deregulation is associated with chronic inflammation, and multifactorial auto-immune disorders. It mediates its biological roles through a hexameric complex composed of IL-6 itself, its receptor IL-6R, and glycoprotein 130 (IL-6/IL-6R/gp130). This complex, in turn, activates different signaling mechanisms (classical and trans-signaling) to execute various biochemical functions. The trans-signaling mechanism activates various pathological routes, like JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt, and regulation of CD4+ T cells and VEGF levels, which cause cancer, multiple sclerosis, rheumatoid arthritis, anemia, inflammatory bowel disease, Crohn's disease, and Alzheimer's disease. Involvement of IL-6 in pathophysiology of these complex diseases makes it an important target for the treatment of these diseases. Though some anti-IL-6 monoclonal antibodies are being used clinically, but their high cost, only parenteral administration, and possibility of immunogenicity have limited their use, and warranted the development of novel small non-peptide molecules as IL-6 inhibitors. In the present report, all molecules reported in literature as IL-6 inhibitors have been classified as IL-6 production, IL-6R, and IL-6 signaling inhibitors. Reports available till date are critically studied to identify important and salient structural features common in these molecules. These analyses would assist medicinal chemists to design novel and potent IL-6 production and signaling inhibitors, through knowledge- and/or computer-based approaches, for the treatment of complex multifactorial diseases.
中文翻译：
IL-6综述：结构，病理生理作用和抑制剂。
白介素6（IL-6）是一种多效性促炎细胞因子。它的失调与慢性炎症和多因素自身免疫疾病有关。它通过由IL-6本身，其受体IL-6R和糖蛋白130（IL-6 / IL-6R / gp130）组成的六聚体复合物介导其生物学作用。反过来，这种复合物激活了不同的信号传导机制（经典信号和反信号传导）来执行各种生化功能。反信号机制激活了各种病理途径，例如JAK / STAT3，Ras / MAPK，PI3K-PKB / Akt以及对CD4 + T细胞和VEGF水平的调节，从而导致癌症，多发性硬化症，类风湿性关节炎，贫血，炎症性肠病，克罗恩氏病和阿尔茨海默氏病。IL-6参与这些复杂疾病的病理生理学使其成为治疗这些疾病的重要目标。尽管一些抗IL-6单克隆抗体在临床上正在使用，但是它们的高成本，仅肠胃外施用以及免疫原性的可能性限制了它们的使用，并保证了新型的非肽小分子作为IL-6抑制剂的开发。在本报告中，文献中报道的所有作为IL-6抑制剂的分子已被分类为IL-6产生，IL-6R和IL-6信号抑制剂。迄今为止，对可用的报告进行了严格的研究，以确定这些分子中常见的重要和显着的结构特征。这些分析将通过基于知识和/或计算机的方法，协助药物化学家设计新颖有效的IL-6产生和信号抑制剂，
更新日期：2020-01-21
中文翻译：
IL-6综述：结构，病理生理作用和抑制剂。
白介素6（IL-6）是一种多效性促炎细胞因子。它的失调与慢性炎症和多因素自身免疫疾病有关。它通过由IL-6本身，其受体IL-6R和糖蛋白130（IL-6 / IL-6R / gp130）组成的六聚体复合物介导其生物学作用。反过来，这种复合物激活了不同的信号传导机制（经典信号和反信号传导）来执行各种生化功能。反信号机制激活了各种病理途径，例如JAK / STAT3，Ras / MAPK，PI3K-PKB / Akt以及对CD4 + T细胞和VEGF水平的调节，从而导致癌症，多发性硬化症，类风湿性关节炎，贫血，炎症性肠病，克罗恩氏病和阿尔茨海默氏病。IL-6参与这些复杂疾病的病理生理学使其成为治疗这些疾病的重要目标。尽管一些抗IL-6单克隆抗体在临床上正在使用，但是它们的高成本，仅肠胃外施用以及免疫原性的可能性限制了它们的使用，并保证了新型的非肽小分子作为IL-6抑制剂的开发。在本报告中，文献中报道的所有作为IL-6抑制剂的分子已被分类为IL-6产生，IL-6R和IL-6信号抑制剂。迄今为止，对可用的报告进行了严格的研究，以确定这些分子中常见的重要和显着的结构特征。这些分析将通过基于知识和/或计算机的方法，协助药物化学家设计新颖有效的IL-6产生和信号抑制剂，
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