从体外到细胞内:一系列新的小分子抗tnf α活性的评价

Aïda Mascret, Hadley Mouhsine, D. Cabrera, C. Ricco, M. S. Veitía, M. Port, J. Zagury
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引用次数: 0

摘要

肿瘤坏死因子α (TNFa)是治疗慢性炎症性疾病如类风湿关节炎或克罗恩病的相关临床靶点。抗tnfa生物疗法用于治疗这些疾病。它们大大改善了病人的生活条件,但也不是没有缺点。它们会产生副作用,比如增加感染的风险,一些患者会对这些生物疗法产生耐药性,而且它们很昂贵。与现有的生物疗法相比,TNFa的小分子抑制剂的缺点更少,副作用更小,没有耐药性,口服给药,并且可能导致更便宜的治疗。目前已知的TNFa直接抑制剂小分子很少,SPD304是He等人在2005年描述的第一个小分子。这些分子都没有显示出有效的活性和低毒性,这是使它们进入临床试验所必需的。Cnam的GBA实验室已经建立了一个旨在寻找新的小分子TNFa抑制剂的项目。在硅对接研究预览导致鉴定潜在的抗tnfa分子。在对接结果的基础上,设计、合成了新的小分子并进行了生物学评价。在这里,我们描述了一系列的30个新合成的化合物的生物学评价其抑制TNFa的能力。这些分子在体外使用两种不同的免疫测定法(结合和转移)和两种不同细胞系的细胞试验进行评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
From In Vitro to In Cellulo: Evaluation of Anti-TNFα Activity of a New Series of Small Molecules
The Tumor Necrosis Factor alpha (TNFa) is a relevant clinical target for the treatment of chronic inflammatory diseases as rheumatoid arthritis or Crohn’s disease. Anti-TNFa biotherapies are used for the treatment of these diseases. They considerably improve patient living conditions but they are not without drawbacks. They cause side effects like accrue risk of infection, some patient develop resistance to these biotherapies and they are expensive. Small molecules inhibitors of TNFa would present fewer disadvantages than existing biotherapies, less side effects, no resistance, oral administration and would probably lead to less expensive treatments. Today only few small molecules are known as direct inhibitors of TNFa, SPD304 was the first small molecule described by He et al in 2005. None of these molecules showed both an efficient activity and a low toxicity, necessary to yield them into clinical trial. The Laboratory GBA of Cnam has set-up a program aiming at finding new small molecules inhibitors of TNFa. A preview in silico docking study led to the identification of potential anti-TNFa molecules. Based on the docking results, new small molecules have been designed, synthetized and biologically evaluated. Herein we describe the biological evaluation of a series of thirty new synthetized compounds for their capacity to inhibit the TNFa. These molecules were evaluated in vitro using two different immuno-assays (binding and shifting) and cell tests on two different cell lines.
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