Small-Molecule Antagonists of the RIG-I Innate Immune Receptor

ACS Chem Biol. 2020 Feb 21;15(2):311-317. doi: 10.1021/acschembio.9b00810. Epub 2020 Jan 27.


The RIG-I receptor plays a key role in the vertebrate innate immune system, where it functions as a sensor for detecting infection by RNA viruses. Although agonists of RIG-I show great potential as antitumor and antimicrobial therapies, antagonists of RIG-I remain undeveloped, despite the role of RIG-I hyperstimulation in a range of diseases, including COPD and autoimmune disorders. There is now a wealth of information on RIG-I structure, enzymatic function, and signaling mechanism that can drive new drug design strategies. Here, we used the enzymatic activity of RIG-I to develop assays for high-throughput screening, SAR, and downstream optimization of RIG-I antagonists. Using this approach, we have developed potent RIG-I antagonists that interact directly with the receptor and which inhibit RIG-I signaling and interferon response in living cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • DEAD Box Protein 58 / antagonists & inhibitors*
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Receptors, Immunologic / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship


  • 4-hydroxy-3,3-dimethyl-2H-benzo(g)indole-2,5(3H)-dione
  • Indoles
  • Receptors, Immunologic
  • RIGI protein, human
  • DEAD Box Protein 58