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

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.

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Fig: Design and rationale of tetrasubstituted imidazole derivatives: The structure of R837 (a selective TLR7 agonist) and R848 (a nonselective TLR7 and TLR8 agonist) are shown. Previous SAR efforts resulted in R848 and R837 mainly focused on the 5-membered azole ring and its substituents. In this work, we broke apart the aminoquinoline ring to introduce more rotatable bonds but maintained the substituents that originally provided TLR8 activity.

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.

Yang, Y., Csakai, A., Jiang, S. et al. Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists. Nat Commun 12, 4351 (2021). https://doi.org/10.1038/s41467-021-24536-4

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