Table 1.
MyD88-dependent TLR4 signaling inhibitors
| Target | Name | Function | BBB | Reference |
|---|---|---|---|---|
| TLR4 | TAK-242 | Binds onto TLR4 on the intracellular side, preventing TLR4 interaction with TIRAP | Permeable | Karimy et al., 2017 25 Matsunaga et al., 2011 67 |
| TLR4 | Curcumin | Targets TLR4, preventing TLR4 dimerization upon ligand binding | Permeable | Zhu et al., 2014 48 |
| TLR4 | Fluoxetine | Mechanism of action remains unknown | Permeable | Liu et al., 2018 68 |
| TLR4 | ApTLR#1 R | Bind directly to TLR4, preventing ligand binding | Permeable | Fernández et al., 2018 45 |
| TLR4 | ApTLR#4 F | Bind directly to TLR4, preventing ligand binding | Permeable | Fernández et al., 2018 45 |
| TLR4-ERK-AKT | Dasatinib | Mechanism of action is unknown but suggested to bind and inhibit TLR4, pERK, and pAKT | Permeable | Ryu et al., 2019 37 |
|
TLR4- TRAF6 |
Resveratrol | Interferes with TLR4 dimerization and mitigates TRAF6 ubiquitination and activation of downstream mediators | Permeable | Zhang et al., 2016 19 Jakus et al., 2013 49 |
| MD-2 | Eritoran | Replaces lipid A binding to MD-2, inhibiting MD-2/TLR4 interaction and downstream signaling | Non- permeable |
Nymo et al., 2016 53 |
| MD-2 | LPS-RS | Interferes with the association of MD-2 with TLR4, preventing ligand binding | Non-permeable | Kawakita et al., 2017 33 |
|
MD-2 & CD-14 |
IAXO-102 | Inhibits the action of MD-2 and CD-14, interfering with ligand presentation to TLR4 | Non-permeable | Kawakita et al., 2017 33 |
| MD-2 | Ciprofloxacin & Levofloxacin | Inhibits TLR4 dimerization by binding the hydrophobic region of MD-2, preventing the MD-2 TLR4 association | Permeable | Zusso et al., 2019 56 |
| MyD88 | T6167923 | Mimics and directly binds to the TIR domain on MyD88, preventing MyD88 homodimerization and further signaling | Unknown | Loiarro et al., 2005 39 Saqib et al., 2018 69 |
| MyD88 | ST2825 | Mimics and directly binds to the TIR domain on MyD88, preventing MyD88 homodimerization and further signaling | Unknown | Olson et al., 2015 38 |
| TAK1 | Dehydroabietic Acid | Inhibits TRAF6 and TAK1 interaction, preventing activation and downstream upregulation of IKK | Unknown | Kim et al., 2019 40 |
| TAK1 | 5z-7-oxozeanenol | Mechanism of action remains unknown | Unknown | Chen et al., 2015 41 Ninomiya-Tsuji et al., 2003 70 |
| NF-κB | Retinoic acid | Inhibits NF-κB activation. | Unknown | Rafa et al., 2017 71 |
| NF-κB | PDTC | Inhibits NF-κB activation. | Permeable | Karimy et al., 2017 25 |
| NF-κB | Quercetin | Inhibits the translocation of NF-κB into the nucleus | Permeable | Bhaskar et al., 2011 52 |
| IKK | BAY 11-7082 | Inhibits IKK activity reducing IκB phosphorylation and subsequent degradation, resulting in attenuated NF-κB activation | Unknown | Pierce et al., 1997 42 |
| TNF-α | Infliximab | Binds to and sequesters TNF-α, preventing propagation of the inflammatory signal | Non-permeable | Nymo et al., 2016 53 |
| IL-1β | Canakinumab | Binds to and sequesters IL-1β, preventing propagation of the inflammatory signal | Non-permeable | Nymo et al., 2016 53 |
| NKCC1 | Bumetanide | Loop diuretic binds and inhibits NKCC1. | Non-permeable | Karimy et al., 2017 25 |
| SPAK | STOCK-1s-50,699 | Binds allosterically to SPAK’s CCT domain, inhibiting binding and activation from upstream kinases | Non-permeable | Karimy et al., 2017 25 |
| SPAK | Closantel | Inhibits SPAK-mediated phosphorylation of NKCC1. | Semi-permeable | Karimy et al., 2017 25 Zhang et al., 2020 44 |
| SPAK | ZT-1a | Binds allosterically to SPAK’s CCT domain, inhibiting binding and activation from upstream kinases | Semi-permeable | Zhang et al., 2020 44 |
| Unknown | Heparin | Unknown | Permeable | Hayman et al. 2017 61 |