Small-molecule inhibitors of the TLR3/dsRNA complex

J Am Chem Soc. 2011 Mar 23;133(11):3764-7. doi: 10.1021/ja111312h. Epub 2011 Feb 28.


The protein-RNA interface has been regarded as "undruggable" despite its importance in many biological processes. The toll-like receptor 3 (TLR3)/double-stranded RNA (dsRNA) complex provides an exciting target for a number of infectious diseases and cancers. We describe the development of a series of small-molecule probes that were shown to be competitive inhibitors of dsRNA binding to TLR3 with high affinity and specificity. In a multitude of assays, compound 4a was profiled as a potent antagonist to TLR3 signaling and also repressed the expression of downstream signaling pathways mediated by the TLR3/dsRNA complex, including TNF-α and IL-1β.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Mice
  • Models, Molecular
  • RNA, Double-Stranded / antagonists & inhibitors*
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / metabolism
  • Signal Transduction
  • Toll-Like Receptor 3 / antagonists & inhibitors*
  • Toll-Like Receptor 3 / chemistry
  • Toll-Like Receptor 3 / metabolism


  • RNA, Double-Stranded
  • Toll-Like Receptor 3