Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.
Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity.
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DOI：
10.1021/acs.jmedchem.5b01087
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发表时间：
2015-10-08
影响因子：
7.3
通讯作者：
David SA
中科院分区：
文献类型：
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作者：
Beesu M;Caruso G;Salyer AC;Khetani KK;Sil D;Weerasinghe M;Tanji H;Ohto U;Shimizu T;David SA
人Toll样受体8（hTLR 8）在髓样树突细胞、单核细胞和单核细胞衍生的树突细胞中表达。TLR 8激动剂的参与引起了有利于1型辅助T细胞发育的独特细胞因子谱。与双重TLR 7/8-激动剂N1-取代的咪唑并喹啉的两个区域异构体共结晶的hTLR 8的胞外域的晶体结构在其与hTLR 8的结合位点的相互作用中显示出细微的差异。我们假设，以前报道的同类最佳纯TLR 8激动剂3-戊基喹啉-2-胺的效力可以通过“设计”官能团来进一步增强，这些官能团将模拟我们在晶体结构中观察到的关键分子间相互作用。我们进行了一个集中的探索，在所有可能的位置上用烷基氨基修饰喹啉核。这些研究已经鉴定出一种新的TLR 8激动剂，其效力是母体化合物的20倍，并且在兔免疫模型中显示出突出的佐剂活性。
Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.