Toll样受体（Toll-like receptors，TLRs）是进化保守的天然免疫模式识别受体，能够识别外源的病原菌相关分子模式（Pathogen-associated molecular patterns，PAMPs）、内源的损害相关分子模式（Damage-associated molecular patterns，DAMPs）和异源物相关分子模式（Xenobiotic-associated molecular patterns），诱导炎症免疫反应。其中，TLR4（Toll-like receptor 4）是目前研究最为广泛的Toll样受体之一，TLR4是脂多糖（lipopoiysaccharide，LPS）的主要受体，LPS激活的TLR4信号通路在炎症信号的传递中发挥着重要作用，而此信号转导需要通过LPS与TLR4及其附属蛋白髓样分化因子2（myeloid differentiation factor 2，MD-2）的相互作用来实现。因此，TLR4/MD-2成为炎症反应和免疫调控最重要的研究热点。本文综述靶向TLR4/MD-2的小分子激动剂和抑制剂的研究进展，以进一步理解TLR4小分子调节剂与其相互作用的复杂性，帮助靶向TLR4/MD-2的免疫调节剂药物发现。
Toll-like receptors(TLRs) are evolutionarily conserved innate immunity receptor proteins that detect pathogen-associated molecular patterns(PAMPs), danger-associated molecular patterns(DAMPs) and xenobiotic-associated molecular patterns(XAMPs), triggering inflammatory responses. TLR4 is the main receptor for bacterial lipopolysaccharide(LPS) and the accessory protein myeloid differentiation factor 2(MD-2) is responsible for ligand recognition. LPS binding induces(TLR4-MD-2-LPS)2 and TLR4/MD-2 complex dimeriztion, which activates TLR4 signaling and produce pro-inflammatory factors. The dysregulation of innate immune TLR4 signaling contributes to numerous pathological diseases. Therefore, TLR4/MD-2 is emerging as an important drug discovery target. In this review, we summarize the up-to-date discovery of TLR4 small molecule modulators and provide insights into future drug discovery, which will be interesting to colleagues major in chemical biology, medicinal chemistry, signal transduction and translational medicine.
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