Li Jing, Csakai Adam, Jin Jialin, Zhang Fengchun, Yin Hang
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100032, China.
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, 80309-0596, USA.
ChemMedChem. 2016 Jan 19;11(2):154-65. doi: 10.1002/cmdc.201500188. Epub 2015 Jul 1.
Toll-like receptors (TLRs) have been shown to play an important role in the immune system, which warrants study of their remarkable potential as pharmacological targets. Activation of TLRs requires participation from specific pathogen-associated molecular patterns (PAMPs) and accessory proteins such as myeloid differentiation protein 2 (MD2), lipopolysaccharide binding protein (LBP), and cluster differentiation antigen 14 (CD14). Assembly of the TLR4-MD2-LPS complex is essential in TLR4 activation. Recent studies have revealed that TLR4 activation is a significant trigger of signal transmission pathways in the nervous system, which could result in chronic pain as well as opioid tolerance and dependence. Researchers of the molecular structure of TLRs and their accessory proteins have opened a door to syntheses of TLRs agonists and antagonists, such as eritoran. Small-molecule modulators of TLR4, such as MD2-I and tricyclic antidepressants, offer more promising prospects than peptides, given their convenience in oral administration and lower cost. Herein we mainly discuss the mechanisms and clinical prospects of TLR4 agonists and antagonists.
Toll样受体（TLRs）已被证明在免疫系统中发挥重要作用，这使得研究其作为药理学靶点的巨大潜力很有必要。TLRs的激活需要特定的病原体相关分子模式（PAMPs）以及诸如髓样分化蛋白2（MD2）、脂多糖结合蛋白（LBP）和分化簇抗原14（CD14）等辅助蛋白的参与。TLR4-MD2-LPS复合物的组装在TLR4激活中至关重要。最近的研究表明，TLR4激活是神经系统信号传导途径的重要触发因素，这可能导致慢性疼痛以及阿片类药物耐受性和依赖性。TLRs及其辅助蛋白分子结构的研究人员为TLRs激动剂和拮抗剂（如依替膦）的合成打开了一扇门。鉴于小分子TLR4调节剂（如MD2-I和三环类抗抑郁药）口服给药方便且成本较低，它们比肽类更具前景。在此我们主要讨论TLR4激动剂和拮抗剂的作用机制及临床前景。
