Toll-like receptor 2 (TLR2) antagonists are key therapeutic targets because they inhibit several inflammatory diseases caused by surplus TLR2 activation. In this study, we identified two novel nonpeptide TLR2 antagonists, C11 and C13, through pharmacophore-based virtual screening. At 10 μm, the level of interleukin (IL)-8 inhibition by C13 and C11 in human embryonic kidney TLR2 overexpressing cells was comparable to the commercially available TLR2 inhibitor CU-CPT22. In addition, C11 and C13 acted in mouse macrophage-like RAW 264.7 cells as TLR2-specific inhibitors and did not suppress the tumor necrosis factor-α induction by TLR3 and TLR4 activators. Moreover, the two identified compounds bound directly to the human recombinant TLR2 ectodomain, during surface plasmon resonance analysis, and did not affect cell viability in a 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. In total, two virtually screened molecules, C11 and C13, were experimentally proven to be effective as TLR2 antagonists, and thus will provide new insights into the structure of TLR2 antagonists, and pave the way for the development of TLR2-targeted drug molecules.
Bibliographical noteFunding Information:
This work was supported by the Mid-Career Researcher Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (NRF-2015R1A2A2A09001059), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C1992). This work was also partially supported by a grant from the National Research Foundation of Korea (NRF 2012-0006687).
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology