摘要
肿瘤坏死因子(TNF,TNF-α,cachectin)是一种具有多种生物效应的多效促炎细胞因子,它们中许多还未研究透彻。虽然三十多年前,TNF最初被认为是抗肿瘤药,但当前的知识认为它是免疫系统内稳态的核心。TNF在宿主抗感染中发挥关键作用,同时也抑制自体免疫性疾病。但是,通过引导与急慢性炎症反应相关基因的表达,TNF生产过剩也会产生有害影响。这些炎症反应包括哮喘、风湿性关节炎、克罗恩病和牛皮藓。用生物制品可以直接抑制TNF,如单克隆抗体和循环TNF受体结构,能有效治疗这些疾病,这同时也验证了这种促炎性细胞因子的抑制是有效的治疗手段。但这些生物疗法也存在缺陷,如高成本和诱使产生自身抗体。如此,能调节TNF产生或信号通路的小分子药物的开发是药物化学的主要挑战。过去二十年里,我们致力于能口服且价廉的该种抑制剂的开发。这篇综述着重讲述了TNF表达、加工、与受体结合和直接抑制等不同层面上,调节这种细胞因子活性的化合物的发展近况。这些方法将被比较和讨论。
关键词: 细胞因子,炎症,蛋白质-蛋白质相互作用,TNF,TNF受体,TNF-TNFR相互作用。
Current Medicinal Chemistry
Title:Small Molecules as Anti-TNF Drugs
Volume: 22 Issue: 25
Author(s): Victoria Richmond, Flavia M. Michelini, Carlos A. Bueno, Laura E. Alche and Javier A. Ramirez
Affiliation:
关键词: 细胞因子,炎症,蛋白质-蛋白质相互作用,TNF,TNF受体,TNF-TNFR相互作用。
摘要: Tumor necrosis factor (TNF, TNF-α, cachectin) is a pleiotropic, proinflammatory cytokine with multiple biological effects, many of which are not yet fully understood. Although TNF was initially described as an anti-tumor agent more than three decades ago, current knowledge places it central to immune system homeostasis. TNF plays a critical role in host defense against infection, as well as an inhibitory role in autoimmune disease. However, TNF overproduction generates deleterious effects by inducing the transcription of genes involved in acute and chronic inflammatory responses including asthma, rheumatoid arthritis, Crohn´s disease, and psoriasis. Direct inhibition of TNF by biologics, such as monoclonal antibodies and circulating TNF receptor constructs, has produced effective treatments for these disorders and validated the inhibition of this proinflammatory cytokine as an effective therapy. Unfortunately, these biological therapies suffer from several drawbacks, including high cost and the induction of autoantibody production. Thus, the development of small molecules able to modulate TNF production or signaling pathways remains a central challenge in Medicinal Chemistry. Considerable efforts have been made over the past two decades to develop such inhibitors, which could potentially be administered orally and would presumably be cheaper. This review is focused on the recent development of compounds that modulate the activity of this cytokine by acting at different levels, such as TNF expression, processing, binding to its receptors and direct inhibition. These approaches will be compared and discussed.
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Cite this article as:
Victoria Richmond, Flavia M. Michelini, Carlos A. Bueno, Laura E. Alche and Javier A. Ramirez , Small Molecules as Anti-TNF Drugs, Current Medicinal Chemistry 2015; 22 (25) . https://dx.doi.org/10.2174/0929867322666150729115553
DOI https://dx.doi.org/10.2174/0929867322666150729115553 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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