Identification of High-Potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines.
The induction of toll-like receptor 7 (TLR7)-dependent type I interferons (IFN-α/β) from plasmacytoid dendritic cells as well as the production of TLR8-dependent type II interferon (IFN-γ), TNF-α, and IL-12 in myeloid dendritic cells are of importance in generating T helper-1 biased adaptive immune responses. In an effort to identify novel dual TLR7/TLR8-active compounds, we undertook structure-activity relationship studies in pyrimidine 2,4-diamines, focusing on substituents at C5. Several analogues substituted with aminopropyl appendages at C5 displayed dominant TLR8-agonistic activity. N4-Butyl-6-methyl-5-(3-morpholinopropyl)pyrimidine-2,4-diamine was found to be a very potent dual TLR7/TLR8 agonist. Employing novel cytokine reporter cell assays, we verified that potency at TLR7 correlates with IFN-α/β production in human blood, whereas IFN-γ and TNF-α induction is largely TLR8-dependent. Dual TLR7/TLR8 agonists markedly upregulate CD80 expression in multiple dendritic cell subsets, providing insight into the immunological basis for the superior adjuvantic properties of such innate immune stimuli.
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Mallesh
M
Beesu
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Alex C D
AC
Salyer
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Michael J H
MJ
Brush
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Kathryn L
KL
Trautman
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Justin K
JK
Hill
Department of Medicinal Chemistry, University of Minnesota , Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Sunil A
0000-0003-1655-4641
SA
David
D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
D003959:Diamines; D011743:Pyrimidines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8