Identification of High-Potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines
| Autor: | Alex C. D. Salyer, Justin K. Hill, Sunil A. David, Kathryn L. Trautman, Mallesh Beesu, Michael J. H. Brush |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Stereochemistry medicine.medical_treatment Cell Diamines 03 medical and health sciences 0302 clinical medicine Immune system Drug Discovery medicine Humans Receptor Chemistry TLR7 Dendritic cell Molecular biology 030104 developmental biology medicine.anatomical_structure Cytokine Pyrimidines Toll-Like Receptor 7 Toll-Like Receptor 8 030220 oncology & carcinogenesis Molecular Medicine CD80 |
| Zdroj: | Journal of medicinal chemistry. 60(5) |
| ISSN: | 1520-4804 |
| Popis: | 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 i... |
| Databáze: | OpenAIRE |
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