Tetrasubstituted imidazoles as incognito Toll-like receptor 8\u2009a(nta)gonists

Yi Yang,Shuangshuang Jiang,Subada Soti,Lindsey Broadwell,Hiromi Tanji,Chengrui Shi,Torey Jones,Adam Csakai,Umeharu Ohto,Yaohui Fang,Kentaro Sakaniwa,Shu Shen,Fei Deng,Toshiyuki Shimizu,Christina Smith,Hang Yin,Jian Huang

doi:10.1038/s41467-021-24536-4

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.

Highlights

Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs derived from viruses
We found that the production of IFN-α was strongly and synergistically upregulated in peripheral blood mononuclear cells (PBMCs) when co-treated with ORN06 and CU-CPD107 (Fig. 3f), which was in good agreement with the results shown in HEK-Blue hTLR8 cells
In the presence of R848, CU-CPD107 acted as a TLR8 signaling inhibitor

Summary

Introduction

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. Their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. While TLR1, 2, 4, 5, and 6 expressed on the plasma membrane can recognize extracellular stimuli Once detected, these signals trigger an inflammatory response through transcription factors, such as NF-κB and interferon regulatory factors (IRFs). The immune response is paramount to the host organism’s ability to defend itself against invading pathogens, and underactivation of TLRs leaves the host vulnerable to widespread infection[7]. TLR8 plays an important role in the antiviral immune response through recognition of viral RNA in endocytic compartments[15]

Methods

Results

Conclusion