新型小分子TLR7激动剂AXC-715稳定TLR7二聚体并显示广谱抗病毒活性
A Novel Small-Molecule TLR7 Agonist AXC-715 Stabilizes TLR7 Dimerization and Exhibits Broad-Spectrum Antiviral Activity.
摘要(中文译文)
Toll样受体7（TLR7）激动作用为抗病毒干预提供了一条有前景的途径。本研究表征了AXC-715，一种新型小分子激动剂，可选择性靶向TLR7以引发广谱抗病毒效应。对AXC-715-hTLR7复合物（PDB ID：5GMH）的结构分析阐明了受体激活的分子基础。AXC-715占据TLR7单体的界面，与D555和T586形成关键氢键，并与F408、V381和L557产生π-π和π-烷基相互作用。这些相互作用有效促进并稳定了TLR7活性二聚体构象。在功能上，AXC-715以P65依赖的方式激活NF-κB信号通路，且在PK-15或THP-1细胞中不诱导细胞毒性。体外实验表明，AXC-715通过特异性损害病毒复制，而非吸附、进入、组装或释放过程，有效抑制伪狂犬病病毒（PRV）和水疱性口炎病毒（VSV）的复制。在TLR7敲除的PK-15细胞中，抗病毒效应被消除，证实了AXC-715对靶向TLR7信号的严格依赖性。这些发现凸显了AXC-715作为一种有效的TLR7激动剂，通过稳定受体二聚化来抑制病毒复制，为开发基于TLR7的抗病毒治疗药物提供了有价值的框架。
Abstract
Toll-like receptor 7 (TLR7) agonism offers a promising avenue for antiviral intervention. This study characterizes AXC-715, a novel small-molecule agonist that selectively targets TLR7 to elicit broad-spectrum antiviral effects. Structural analysis of the AXC-715-hTLR7 complex (PDB ID: 5GMH) elucidates the molecular basis of receptor activation. AXC-715 occupies the interface of TLR7 monomers, establishing critical hydrogen bonds with D555 and T586, alongside π-π and π-alkyl interactions with F408, V381, and L557. These interactions effectively promote and stabilize the active TLR7 dimeric conformation. Functionally, AXC-715 activates NF-κB signaling in a P65-dependent manner without inducing cytotoxicity in PK-15 or THP-1 cells. In vitro assays demonstrated that AXC-715 potently inhibits the replication of both pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) by specifically impairing viral replication, distinct from adsorption, entry, assembly, or release processes. The antiviral effect was abolished in TLR7-knockout PK-15 cells, confirming the strict dependence of AXC-715 on on-target TLR7 signaling. These findings highlight AXC-715 as a potent TLR7 agonist that stabilizes receptor dimerization to inhibit viral replication, providing a valuable framework for developing TLR7-based antiviral therapeutics.
如何引用
AMA
Chen Yao, Meng-Hua Du, Yan-Jie Ma, Heng Wang, Liu Hang, Zhi-Cheng Li, et al. A Novel Small-Molecule TLR7 Agonist AXC-715 Stabilizes TLR7 Dimerization and Exhibits Broad-Spectrum Antiviral Activity.. Microorganisms. 2026; doi:10.3390/microorganisms14040862.
APA
Chen Yao, Meng-Hua Du, Yan-Jie Ma, Heng Wang, Liu Hang, Zhi-Cheng Li, et al (2026). A Novel Small-Molecule TLR7 Agonist AXC-715 Stabilizes TLR7 Dimerization and Exhibits Broad-Spectrum Antiviral Activity.. Microorganisms. https://doi.org/10.3390/microorganisms14040862
GB/T 7714
Chen Yao, Meng-Hua Du, Yan-Jie Ma, Heng Wang, Liu Hang, Zhi-Cheng Li, et al. A Novel Small-Molecule TLR7 Agonist AXC-715 Stabilizes TLR7 Dimerization and Exhibits Broad-Spectrum Antiviral Activity.[J]. Microorganisms, 2026 doi:10.3390/microorganisms14040862.
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