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INHIBITORS 8
Pattern Recognition Receptor (PRR) Signaling Inhibitors
BX795 - TBK/IKKε Inhibitor
BX795, an aminopyrimidine compound, was developed as an inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1) 1 . It was recently shown to be a
potent inhibitor of the IKK-related kinases, TANK-binding kinase 1 (TBK1) and IKKε, and hence of IRF3 activation and IFN-β production 2 . BX795 inhibits the
catalytic activity of TBK1/IKKε by blocking their phosphorylation.
Chloroquine - Inhibitor of Endosomal Acidification
Chloroquine is a lysosomotropic agent that prevents endosomal acidification 3 . It accumulates inside the acidic parts of the cell, including endosomes and
lysosomes. This accumulation leads to inhibition of lysosomal enzymes that require an acidic pH, and prevents fusion of endosomes and lysosomes. Chloroquine
is commonly used to study the role of endosomal acidification in cellular processes, such as the signaling of intracellular TLRs 4, 5 .
CLI-095 - TLR4 Signaling Inhibitor
CLI095, also known as TAK-242, is a novel cyclohexene derivative that specifically suppresses TLR4 signaling, inhibiting the production of NO and proinflammatory
cytokines 6 . It acts by blocking the signaling mediated by the intracellular domain of TLR4, but not the extracellular domain. It potently suppresses
both ligand-dependent and -independent signaling of TLR4 7 .
Cyclosporin A - Calcineurin inhibitor NEW
Cyclopsporin A is a calcineurin inhibitor that exerts its immunosuppressive effects through the down-regulation of NFAT (nuclear factor of activated T cells)
transcription factor, thus preventing the transcription of T cell effector cytokines 8 . Moreover, NFAT has been implicated in the downstream signaling of
Dectin-1 which is important in the innate immune response against fungal infection 9 . Conversely, it has been demonstrated that inhibition of calcineurin in
macrophages enhances NF-κB activation 10 and can trigger TLR signaling by activating both the MyD88-dependent and the MyD88-independent pathways 11 .
Gefitinib - RIP2 Tyrosine Kinase inhibitor NEW
Gefitinib (also known as Iressa) is a selective inhibitor of epidermal growth factor, a growth factor that plays a pivotal role in the control of cell growth, apoptosis, and
angiogenesis. Recent studies demonstrated that Gefitinib can inhibit NOD2-induced cytokine release and NF-kB activation by inhibiting RIP2 (receptor-interacting
protein 2) tyrosine phosphylation which is critical for activation of NOD2 downsream signaling pathways 12 . Gefitinib is used in the treatment of advanced nonsmall cell
lung cancer 13 .
OxPAPC - TLR2 and TLR4 Inhibitor
OxPAPC (1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine), is an oxidized phospholipid that has been shown to inhibit the signaling induced by
bacterial lipopeptide and lipopolysaccharide (LPS). It acts by competing with CD14, LBP and MD2, the accessory proteins that interact with bacterial lipids,
thus blocking the signaling of TLR2 and TLR4 14, 15 .
Pepinh-MYD - MyD88 inhibitory peptide
Pepinh-MYD is a 26 aa peptide that blocks MyD88 signaling by inhibiting its homodimerization through binding. Pepinh-MYD contains a sequence from the
MyD88 TIR homodimerization domain (RDVLPGT) 16 preceeded by a protein transduction sequence (RQIKIWFQNRMKWKK) derived from antennapedia
which enables the peptide to translocate through the cell membrane 17 . Pepinh-MYD is provided with a control peptide.
Pepinh-TRIF - TRIF inhibitory peptide
Pepinh-TRIF is a 30 aa peptide that blocks TRIF signaling by interfering with TLR-TRIF interaction. Pepinh-TRIF contains the 14 aa that correspond to the
sequence of the BB loop of TRIF (FCEEFQVPGRGELH) 18 linked to the cell-penetrating segment of the antennapedia homoedomain
(RQIKIWFQNRMKWKK) 17 . Pepinh-TRIF is provided with a control peptide.
Polymyxin B - Inhibitor of LPS-induced TLR4 activation
Polymyxin B (PMB) is a cyclic cationic polypeptide antibiotic produced by the soil bacterium Paenibacillus polymixa. PMB blocks the biological effects of Gram
negative LPS (endotoxin) through binding to lipid A, the toxic component of LPS, which is negatively charged 19, 20 . The neutralizing effect of PMB on LPS is
dose-related and specific for LPS 21 . PMB is widely used to eliminate the effects of endotoxin contamination, both in vitro and in vivo.
Rapamycin - mTOR Inhibitor
Rapamycin is an inhibitor of the Ser/Thr protein kinase named "mammalian target of rapamycin" (mTOR) that regulates cell growth and metabolism in
response to environmental cues. mTOR is a downstream target of PI3K, an important actor in TLR signaling 22 . Rapamycin was shown to block TLR2- and
TLR4-mediated expression of TNF-a and IL-6 in neutrophils stimulated with Pam3CSK4 or LPS 23 .
Z-VAD-FMK - Caspase Inhibitor
Z-VAD-FMK is a cell-permeable pan-caspase inhibitor that irreversibly binds to the catalytic site of caspase proteases 24 . The peptide is O-methylated in the
P1 position on aspartic acid, providing enhanced stability and increased cell permeability. Z-VAD-FMK is used in apoptosis studies and also in inflammasome
studies. It is a potent inhibitor of caspase-1 activation in NLRP3-induced cells 25 .
1. Feldman RI. et al., 2005. Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1. J. Biol. Chem., 280: 19867 - 19874. 2. Clark K. et al., 2009. Use of the Pharmacological
Inhibitor BX795 to Study the Regulation and Physiological Roles of TBK1 and I{kappa}B Kinase {epsilon}: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J. Biol.
Chem. 284: 14136 - 14146. 3. Steinman RM. et al., 1983. Endocytosis and the recycling of plasma membrane. J. Cell. Biol. 96:1-27. 4. Rutz, M. et al., 2004. Toll-like receptor 9 binds singlestranded
CpG-DNA in a sequence- and pH-dependent manner. Eur. J. Immunol. 34:2541-2550. 5. Hart OM. et al., 2005.TLR7/8-Mediated Activation of Human NK Cells Results in Accessory
Cell-Dependent IFN-{gamma} Production. J. Immunol., 175: 1636 - 1642. 6. Li M. et al., 2006. A Novel Cyclohexene Derivative, Ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-
1-ene-1-carboxylate (TAK-242), Selectively Inhibits Toll-Like Receptor 4-Mediated Cytokine Production through Suppression of Intracellular Signaling. Mol. Pharmacol., 69: 1288 - 1295.
7. Kawamoto T. et al., 2008. TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 584(1):40-8. 8. Chow CW. et al., 1999.
Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Biol. 19(3): 2300-07. 9. Goodridge et al. 2007. Dectin-1stimulation by Candida albicans yeast or zymosan
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