The toll-like receptors (TLR) are a family of protein that are responsible for pathogen recognition. TLR8 is expressed within the endolysosomal compartmental pathway and it is able to recognize the intracellular pathogens[3]. Motolimod is a novel small molecule TLR8 agonist with EC50 of about 100 nmol/L[4]. The THP-1 cells were treated with motolimod from 3 nM to 10 μM overnight. The IL-1β and IL-18 mRNA level measured by RT-PCR were significantly increased after the treatment of motolimod. The IL-β, caspase-1 and pro-IL-1 protein level were also increased significantly as detected by western blotting assay[5]. The hind paw of C57BL/6 mice was intradermally injected with 50 µg of motolimod and spontaneous pain behaviors were counted every 5 min for 30 min. It was found that the treatment of motolimod could induced lifting, flinching and licking in the first 15 min[6].
作用机制
Motolimod is an ultra-potent TLR8 selective agonist by binding with the TLR-8[7].
Motolimod 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293 cells
0.1, 0.5, 5 µM
12 hours
To investigate the effect of VTX-2337 on ERK activity in HEK293 cells, the results showed that VTX-2337 increased ERK luciferase activity at concentrations of 0.1 and 0.5 µM.
J Exp Med. 2018 Dec 3;215(12):3019-3037.
PBMC
250 nM
18 hours
Enhanced cetuximab-mediated ADCC, results showed that TLR8-stimulated PBMC significantly enhanced specific lysis of cetuximab-coated HNC cells
Cancer Immunol Immunother. 2013 Aug;62(8):1347-57.
NK cells
250 nM
18 hours
TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in the presence of cetuximab
Cancer Immunol Immunother. 2013 Aug;62(8):1347-57.
PBMCs
0.1–2 µM
24 hours
To evaluate the effect of VTX-2337 on cytokine secretion from PBMCs. Results showed that VTX-2337 significantly increased the secretion of IFNγ, TNFα, and IL-1β.
Sci Rep. 2021 Jan 15;11(1):1535.
SQ20B HNSCC cells
2 µM
24 hours
To evaluate the effect of VTX-2337 in combination with cetuximab on T cell and NK cell activation in a co-culture system of SQ20B HNSCC cells with PBMCs. Results showed that VTX-2337 significantly increased the activation of CD4+ and CD8+ T cells, but no enhanced effect was observed when combined with cetuximab. VTX-2337 alone did not increase NK cell activation, but when combined with cetuximab, it significantly increased NK cell activation.
Sci Rep. 2021 Jan 15;11(1):1535.
Motolimod 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
SCCVII/C3H, mEERL/C57Bl/6, TUBO-human EGFR/BALB/c
Intraperitoneal injection
1 mg/kg
Every other day for 2 weeks
To evaluate the anti-tumor effect of VTX-2337 in different mouse models. Results showed that VTX-2337 significantly suppressed tumor growth in all three syngeneic mouse models and significantly prolonged the survival of cetuximab-treated mice. The combination of VTX-2337 with cetuximab significantly increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells.
Sci Rep. 2021 Jan 15;11(1):1535.
Mice
Trigeminal neuropathic pain model
Intra-trigeminal ganglion injection
10, 50, 100 ng
Single injection
To study the effect of VTX-2337 on trigeminal neuropathic pain, results showed that VTX-2337 dose-dependently increased facial pain hypersensitivity.
Neurosci Bull. 2021 Apr;37(4):550-562
Mice
Neuropathic pain model
Intrathecal injection
100 ng
Single injection
To investigate the effect of VTX-2337 on neuropathic pain in mice, the results showed that VTX-2337 increased the mRNA expression of TNF-α, IL-1β, IL-6, and CCL2, indicating that VTX-2337 mediated inflammatory responses through TLR8.
J Exp Med. 2018 Dec 3;215(12):3019-3037.
BALB/c mice
BALB/c mice
Intramuscular injection
2 μg/mouse
Immunized on day 0 and day 7, blood collected on day 5 and day 12
To evaluate whether the combination of Motolimod with CL401 could enhance immune responses, results showed that Motolimod exhibited synergistic effects in enhancing immunogenicity
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