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 552954Primary 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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