TY - JOUR
T1 - Identification of High-Potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines
AU - Beesu, Mallesh
AU - Salyer, Alex C.D.
AU - Brush, Michael J.H.
AU - Trautman, Kathryn L.
AU - Hill, Justin K.
AU - David, Sunil A.
N1 - Funding Information:
This work was supported by NIH/NIAID contract HHSN272201400056C.
PY - 2017/3/9
Y1 - 2017/3/9
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.6b01860
DO - 10.1021/acs.jmedchem.6b01860
M3 - Article
C2 - 28146629
AN - SCOPUS:85015078331
SN - 0022-2623
VL - 60
SP - 2084
EP - 2098
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 5
ER -