7crf | pdb_00007crf
Crystal structure of human TLR8 in complex with CU-CPD107
Structural highlights
Function[TLR8_HUMAN] Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[1] Publication Abstract from PubMedSmall-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. Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists.,Yang Y, Csakai A, Jiang S, Smith C, Tanji H, Huang J, Jones T, Sakaniwa K, Broadwell L, Shi C, Soti S, Ohto U, Fang Y, Shen S, Deng F, Shimizu T, Yin H Nat Commun. 2021 Jul 16;12(1):4351. doi: 10.1038/s41467-021-24536-4. PMID:34272380[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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