R848 is an imidazoquinoline and agonist of Toll-like receptors (TLRs) 7 and 8. It mimics the pathogen-associated molecular patterns that activate immune cells through TLR7 and TLR8, and thereby acts as an immune-response modifier. It demonstrates potent anti-tumor and anti-viral properties (IC₅₀ = 4.2 μM; Seganish et al.) which appear to be mediated predominantly through the induction of cytokines, including interferon (IFN)-α and interleukin (IL)-12 due to stimulation of monocytes, macrophages, and dendritic cells (Bernstein et al.; Hattermann et al.; Nian et al.).
IMMUNOLOGY
· Triggers activation of human B cells, including activation of c-Jun kinase, p38 and NF-κB transcription factors (Bishop et al.).
· Induces proliferation and cytokine production by human CD4+ T cells (Caron et al.).
· Primes human neutrophils for leukotriene B4, prostaglandin E2, and platelet-activating factor biosynthesis (Hattermann et al.).
· Suppresses HIV-1 replication in monocytes (Nian et al.). · Induces expression of IL-12 and IFN-ɣ in mouse and human peripheral blood cell cultures (Wagner et al.).
DIFFERENTIATION
· Targets osteoclast precursors and inhibits their differentiation into osteoclasts via TLR7 (Miyamoto et al.).
· Induces myeloid differentiation of CD34+ hematopoietic progenitor cells, including upregulated expression of cytokines (IL-1β, TNF-α, IL-6, GM-CSF) and CD11c surface marker (Sioud et al.).
IMMUNOLOGY
· Triggers activation of human B cells, including activation of c-Jun kinase, p38 and NF-κB transcription factors (Bishop et al.).
· Induces proliferation and cytokine production by human CD4+ T cells (Caron et al.).
· Primes human neutrophils for leukotriene B4, prostaglandin E2, and platelet-activating factor biosynthesis (Hattermann et al.).
· Suppresses HIV-1 replication in monocytes (Nian et al.). · Induces expression of IL-12 and IFN-ɣ in mouse and human peripheral blood cell cultures (Wagner et al.).
DIFFERENTIATION
· Targets osteoclast precursors and inhibits their differentiation into osteoclasts via TLR7 (Miyamoto et al.).
· Induces myeloid differentiation of CD34+ hematopoietic progenitor cells, including upregulated expression of cytokines (IL-1β, TNF-α, IL-6, GM-CSF) and CD11c surface marker (Sioud et al.).
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Protocols and Documentation
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Resources and Publications
Publications (10)
Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors. ACS medicinal chemistry letters 2015 AUG
Abstract
We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (textgreater100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
R848, a toll-like receptor 7 agonist, inhibits osteoclast differentiation but not survival or bone-resorbing function of mature osteoclasts. Cytotechnology 2012 MAY
Abstract
R848, also known as resiquimod, acts as a ligand for toll-like receptor 7 (TLR7) and activates immune cells. In this study, we examined the effects of R848 on differentiation, survival, and bone-resorbing function of osteoclasts. R848 inhibited osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) and human peripheral blood-derived monocytes induced by receptor activator of NF-κB ligand in a dose-dependent manner. In addition, it inhibited mouse osteoclast differentiation induced in cocultures of bone marrow cells and osteoblasts in the presence of dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. However, R848 did not affect the survival or bone-resorbing activity of mouse mature osteoclasts. R848 also upregulated the mRNA expression levels of interleukin (IL)-6, IL-12, interferon (IFN)-γ, and inducible nitric oxide synthase in mouse BMMs expressing TLR7. IFN-β was consistently expressed in the BMMs and addition of neutralizing antibodies against IFN-β to the cultures partially recovered osteoclast differentiation inhibited by R848. These results suggest that R848 targets osteoclast precursors and inhibits their differentiation into osteoclasts via TLR7.
R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes. BMC infectious diseases 2012 JAN
Abstract
BACKGROUND Toll-like receptors (TLR) 7 and 8 are important in single-stranded viral RNA recognition and may play a role in HIV infection and disease progression. We analyzed TLR7/8 expression and signaling in monocytes from HIV-infected and uninfected subjects to investigate a pathway with new potential for the suppression of HIV replication. METHODS Eighty-one HIV-infected and uninfected subjects from Liaoning and Henan provinces in China participated in this study. Monocytes were isolated from subjects' peripheral blood mononuclear cells by magnetic bead selection. TLR7 and TLR8 mRNA was measured using quantitative real-time reverse transcriptase PCR. R-848 (resiquimod) was used as a ligand for TLR7 and TLR8 in order to 1) assess TLR7/8-mediated monocyte responsiveness as indicated by IL-12 p40 and TNF-α secretion and 2) to examine HIV replication in cultured monocytes in the presence of R-848. RESULTS We found that expression of TLR7/8 mRNA in peripheral blood monocytes decreased with disease progression. TLR7 expression was decreased with stimulation with the TLR7/8 agonist, R-848, in vitro, whereas TLR8 expression was unaffected. Following R-848 stimulation, monocytes from HIV-infected subjects produced significantly less TNF-α than those from uninfected subjects, but trended towards greater production of IL-12 than stimulated monocytes from uninfected subjects. R-848 stimulation also suppressed HIV replication in cultured monocytes. CONCLUSIONS Our study provides evidence that the TLR7 and TLR8 triggering can suppress HIV replication in monocytes and lead to postpone HIV disease progression, thereby offering novel targets for immunomodulatory therapy.
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