Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic specificity, increased efficiency and reduced adverse effects. Therefore, the identification of such modulators as drug candidates is highly desirable. Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors (GPCRs). The biased signaling modulation of non-GPCR receptors has yet to be exploited. Toll-like receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling pathways. Moreover, the dysregulation of TLR4 contributes to numerous diseases, which highlights the importance of biased modulator development targeting TLR4. In this review, we aim to provide an overview of the recent progress in the discovery of biased modulators of TLR4. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates. The discovery of biased modulators of TLR4 would provide insight for the future development of biased modulators for other non-GPCR receptors.

偏向药理学调节剂提供潜在的治疗益处，包括更大的药效特异性、提高效率和减少不良反应。因此，将这些调节剂鉴定为候选药物是非常可取的。目前，主要关注针对 G 蛋白偶联受体 (GPCRs) 的偏向信号调节剂。非 GPCR 受体的偏向信号调制尚未被开发。Toll 样受体 4 (TLR4) 就是这样一种非 GPCR 受体，它涉及 MyD88 依赖性和 TRIF 依赖性信号通路。此外，TLR4 的失调会导致多种疾病，这突出了针对 TLR4 的偏向调节剂开发的重要性。在这篇综述中，我们旨在概述发现 TLR4 偏向调节剂的最新进展。还概述了发现 TLR4 偏向调制器的挑战和方法。偏向调节 TLR4 信号轴的小分子不仅提供了微调受体构象和信号的探针，而且还提供了识别有前景的候选药物的机会。TLR4 偏向调节剂的发现将为未来开发其他非 GPCR 受体的偏向调节剂提供见解。