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PDBsum entry 5awd
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Immune system
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PDB id
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5awd
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of human tlr8-Specific agonists with augmented potency and adjuvanticity.
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Authors
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M.Beesu,
G.Caruso,
A.C.Salyer,
K.K.Khetani,
D.Sil,
M.Weerasinghe,
H.Tanji,
U.Ohto,
T.Shimizu,
S.A.David.
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Ref.
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J Med Chem, 2015,
58,
7833-7849.
[DOI no: ]
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PubMed id
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Abstract
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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.
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