小分子抑制TNF-α的作用
Molly M He1, Annemarie Stroustrup Smith, Johan D Oslob
1Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
概括
一种新型的小分子抑制剂通过促进其子单元解离来破坏瘤亡因子α (TNF-α). 这种化合物有效地抑制TNF-α活性,提供了一个新的治疗途径.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 瘤亡因子α (TNF-α) 是一种关键的炎症性细胞因子,与各种疾病有关.
- TNF-α作为三元蛋白的功能,其活性取决于这个四元结构.
研究的目的:
- 为了识别和表征一种向TNF-alpha三元体的小分子抑制剂.
- 阐明抑制剂破坏TNF-α结构和功能的机制.
主要方法:
- 用生物化学和基于细胞的测试来评估TNF-α抑制活性.
- 采用X射线晶体学来确定抑制的结构基础.
主要成果:
- 在生物化学和基于细胞的测试中,分别发现了一种新型小分子,抑制TNF-alpha,其中位抑制度为22微米和4.6微米.
- 该化合物加速TNF-α亚单元解离的600倍,导致三元体分解.
- X射线结晶学显示,该抑制剂与TNF-alpha子单元的二分体结合,取代一个子单元.
结论:
- 这项研究提出了一种小分子抑制剂,可以有效地分解TNF-alpha三元体.
- 该机制涉及与TNF-alpha子单元的直接相互作用,导致功能抑制.
- 这种抑制剂代表了TNF-α介导疾病的有前途的治疗策略.
更多相关视频
07:49Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
10:21Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
相关概念视频
NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
T Cell Types and Functions
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab (Humira),...
