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Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists

Author

Listed:
  • Yi Yang

    (Tsinghua University)

  • Adam Csakai

    (University of Colorado Boulder)

  • Shuangshuang Jiang

    (Tsinghua University)

  • Christina Smith

    (University of Colorado Boulder)

  • Hiromi Tanji

    (The University of Tokyo)

  • Jian Huang

    (Tsinghua University)

  • Torey Jones

    (University of Colorado Boulder)

  • Kentaro Sakaniwa

    (The University of Tokyo)

  • Lindsey Broadwell

    (University of Colorado Boulder)

  • Chengrui Shi

    (Tsinghua University)

  • Subada Soti

    (University of Colorado Boulder)

  • Umeharu Ohto

    (The University of Tokyo)

  • Yaohui Fang

    (Chinese Academy of Sciences)

  • Shu Shen

    (Chinese Academy of Sciences)

  • Fei Deng

    (Chinese Academy of Sciences)

  • Toshiyuki Shimizu

    (The University of Tokyo)

  • Hang Yin

    (Tsinghua University
    University of Colorado Boulder)

Abstract

Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107’s unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs.

Suggested Citation

  • Yi Yang & Adam Csakai & Shuangshuang Jiang & Christina Smith & Hiromi Tanji & Jian Huang & Torey Jones & Kentaro Sakaniwa & Lindsey Broadwell & Chengrui Shi & Subada Soti & Umeharu Ohto & Yaohui Fang , 2021. "Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24536-4
    DOI: 10.1038/s41467-021-24536-4
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