TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules
Molecular Pharmacology, ISSN: 0026-895X, Vol: 79, Issue: 1, Page: 34-41
2011
- 467Citations
- 354Captures
- 1Mentions
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Metrics Details
- Citations467
- Citation Indexes466
- 466
- CrossRef455
- Policy Citations1
- 1
- Captures354
- Readers354
- 354
- Mentions1
- References1
- 1
Article Description
TAK-242 (resatorvid), a small-molecule–specific inhibitor of Toll-like receptor (TLR) 4 signaling, inhibits the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4. Cys747 in TLR4 has been identified previously as the binding site of TAK-242. However, the mechanism by which TAK-242 inhibits TLR4 signaling after binding to TLR4 remains unknown. The present study demonstrated, using coimmunoprecipitation, that TAK-242 interferes with protein-protein interactions between TLR4 and its adaptor molecules. Among 10 different human TLRs, TAK-242 selectively bound to TLR4. The time course of the inhibitory effect of TAK-242 on inflammatory mediator production corresponded to that of the binding of TAK-242 to TLR4. TAK-242 inhibited the association of TLR4 with Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) or Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β-related adaptor molecule (TRAM) in human embryonic kidney (HEK) 293 cells overexpressing TLR4, MD-2, and TIRAP or TRAM, respectively. TAK-242 inhibited the TIRAP-mediated activation of nuclear factor κB (NF-κB) and the TRAM-mediated activation of NF-κB and interferon-sensitive response element in HEK293 cells stably expressing TLR4, MD-2, and CD14. The activation of endogenous interleukin-1 receptor-associated kinase in RAW264.7 cells was also inhibited by TAK-242 treatment. These findings suggest that TAK-242 binds selectively to TLR4 and subsequently disrupts the interaction of TLR4 with adaptor molecules, thereby inhibiting TLR4 signal transduction and its downstream signaling events. This work proposes a novel paradigm of a small molecule capable of disrupting protein-protein interactions.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0026895X24028554; http://dx.doi.org/10.1124/mol.110.068064; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=78651300299&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/20881006; https://linkinghub.elsevier.com/retrieve/pii/S0026895X24028554; https://dx.doi.org/10.1124/mol.110.068064; https://molpharm.aspetjournals.org/content/79/1/34
Elsevier BV
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