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Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
- Source :
- Nature Communications, Nature Communications, Vol 12, Iss 1, Pp 1-9 (2021)
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.<br />Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Subjects :
- Agonist
genetic structures
medicine.drug_class
Science
Inflammatory response
General Physics and Astronomy
Medicinal chemistry
Inflammation
Mechanism of action
Calorimetry
behavioral disciplines and activities
01 natural sciences
Article
General Biochemistry, Genetics and Molecular Biology
Structure-Activity Relationship
03 medical and health sciences
X-Ray Diffraction
medicine
Humans
Drug discovery and development
030304 developmental biology
0303 health sciences
Toll-like receptor
Multidisciplinary
Innate immune system
010405 organic chemistry
business.industry
Small molecules
Imidazoles
General Chemistry
TLR8
Tlr agonists
Recombinant Proteins
Toll-like receptors
0104 chemical sciences
Molecular Docking Simulation
HEK293 Cells
nervous system
Toll-Like Receptor 8
Quinolines
Cancer research
RNA
medicine.symptom
business
psychological phenomena and processes
Signal Transduction
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....6775b5093b3ed18e55a31f0540caf8d3