| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T48703 | ||||
| Target Name | Toll-like receptor 8 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | CPG 52364 | Drug Info | IC50 = 35 nM | ||
| Resiquimod | Drug Info | EC50 = 1 nM | [552954] | ||
| Action against Disease Model | CPG 52364 | In vitro experiments with DNA, RNA or SLE patient immune complexes stimulated h uMan cells that express h uMan TLR7, TLR8, and/or TLR9 and in vivo experiments with TLR agonist-treated mice have demonstrated that CPG 52364 is a potent and specific inhibitor of murine TLR7 and TLR9 and h uMan TLR7, TLR8, and TLR9. Furthermore, CPG 52364 shows activity in the spontaneous lupus murine model, MRL lpr/lpr mice, as measured by reduction in titers of anti-double-stranded DNA antibody, a common clinical correlate of SLE. CPG 52364 is well tolerated in preclinical animal testing. | Drug Info | ||
| The Effect of Target Knockout, Knockdown or Genetic Variations | Using HEK293 cells transfected with murine TLR7 or TLR8 and a NF-kappaB luciferase reporter, we demonstrated that stimulation of TLR8-, but not TLR7-, transfected cells with either VV or VV DNA resulted in substantial NF-kappaB activation, and that siRNA-mediated knockdown of TLR8 expression in pDCs led to a complete ablation of VV-induced type I IFN production. We further identified that the VV genome was rich in poly(A)/T sequences, and synthetic poly(A) and poly T oligodeoxynucleotides were capable of activating pDCs in a TLR8-dependent manner. In vivo, TLR8-MyD88-dependent pDC activation played a critical role in innate immune control of VV infection. Collectively, our data are unique in demonstrating that TLR8 is required for sensing poly(A)/T-rich DNA in pDCs, and that murine TLR8 is functional in the context of a viral infection | ||||
| References | |||||
| Ref 552954 | Primary leukocyte screens for innate immune agonists. J Biomol Screen. 2009 Jul;14(6):723-30. doi: 10.1177/1087057109335325. Epub 2009 Jun 12. | ||||
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