Molecular Determinants of GS-9620-Dependent TLR7 Activation
Molecular Determinants of GS-9620-Dependent TLR7 Activation
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DOI：
10.1371/journal.pone.0146835
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发表时间：
2016-01-19
期刊：
影响因子：
3.7
通讯作者：
Pflanz, Stefan
中科院分区：
文献类型：
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作者：
Rebbapragada, Indrani;Birkus, Gabriel;Pflanz, Stefan
GS-9620是一种口服toll样受体（TLR） 7激动剂，目前正在临床研究中评估用于治疗慢性HBV和HIV患者。GS-9620在土拨鼠和黑猩猩慢性肝炎病毒感染的临床前模型中显示出抗病毒效果。然而，gs -9620依赖性TLR7激活的分子决定因素尚未明确。本文的研究阐明了GS-9620的亚细胞分布，并利用结构引导的突变分析表征了其与人类TLR7的分子相互作用。基于我们的研究结果，我们建立了一个与GS-9620结合的TLR7分子模型。我们还确定了一些编码snp对gs -9620依赖性TLR7激活没有影响。此外，我们的研究提供了证据，证明TLR7以不依赖于配体的低聚态存在，GS-9620激活TLR7可能与化合物诱导的构象变化有关。最后，我们证明了原代浆细胞样树突状细胞中nf - κ B和Akt通路的激活是对GS-9620刺激的直接下游细胞反应。本文提供的数据进一步加深了我们对GS-9620激活TLR7的分子参数的理解，更广泛地说，是由核/潮汐相关配体激活的。
GS-9620 is an orally administered agonist of Toll-like receptor (TLR) 7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-kappa B and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands.