期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 19, 页码 7833-7849出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01087
关键词
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资金
- NIH/NIAID [HSN272200900033C, HHSN272201400056C]
- NIH [S10RR024664]
- NSF Major Research Instrumentation Grant [0320648]
- Grants-in-Aid for Scientific Research [15J12485] Funding Source: KAKEN
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-2amine, 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 similar to 20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization.
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