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

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, Shu Shen, Fei Deng, Toshiyuki Shimizu and Hang Yin ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24536-4

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