Department of Biotechnology & Biosciences, University of Milano-Bicocca; Piazza della Scienza, 2; 20126 Milano, Italy.
Future Med Chem. 2018 Feb;10(4):461-476. doi: 10.4155/fmc-2017-0172. Epub 2018 Jan 30.
Activation or inhibition of TLR4 by small molecules will provide in the next few years a new generation of therapeutics. TLR4 stimulation (agonism) by high-affinity ligands mimicking lipid A gave vaccine adjuvants with improved specificity and efficacy that have been licensed and entered into the market. TLR4 inhibition (antagonism) prevents cytokine production at a very early stage; this is in principle a more efficient method to block inflammatory diseases compared to cytokines neutralization by antibodies. Advances in TLR4 modulation by drug-like small molecules achieved in the last years are reviewed. Recently discovered TLR4 agonists and antagonists of natural and synthetic origin are presented, and their mechanism of action and structure-activity relationship are discussed.
在未来几年，小分子对 TLR4 的激活或抑制作用将提供新一代的治疗方法。高亲和力配体模拟脂多糖对 TLR4 的刺激（激动作用）产生了具有改善的特异性和功效的疫苗佐剂，这些佐剂已经获得许可并进入市场。TLR4 抑制（拮抗作用）可在非常早期阻止细胞因子的产生；与抗体中和细胞因子相比，这在原则上是一种更有效的方法来阻断炎症性疾病。本文综述了近年来在 TLR4 调节方面取得的类似药物的小分子进展。介绍了最近发现的天然和合成来源的 TLR4 激动剂和拮抗剂，并讨论了它们的作用机制和构效关系。
