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@ARTICLE{ribar:430316,
author = {Šribar, Dora and Grabowski, Maria and Murgueitio, Manuela
S. and Bermudez, Marcel and Weindl, Günther and Wolber,
Gerhard},
title = {{I}dentification and characterization of a novel chemotype
for human {TLR}8 inhibitors},
journal = {European journal of medicinal chemistry},
volume = {179},
issn = {0223-5234},
address = {Amsterdam [u.a.]},
publisher = {Elsevier10887},
reportid = {PUBDB-2020-00008},
pages = {744-752},
year = {2019},
note = {© Elsevier Masson SAS. ; Final published version in
progress; Post referee fulltext in progress; Embargo 12
months from publication},
abstract = {The endosomal Toll-like receptor 8 (TLR8) recognizes
single-stranded RNA and initiates early inflammatory
responses. Despite the importance of endosomal TLRs for
human host defense against microbial pathogens, extensive
activation may contribute to autoimmune and inflammatory
diseases. In contrast to the recent progress made in the
development of modulators of plasma membrane-bound TLRs,
little is known about endosomal TLR modulation and very few
TLR8 inhibitors have been reported. In this study, we
discovered and validated novel small-molecule TLR8
inhibitors. Fourteen potential TLR8 modulators were
experimentally validated in HEK293T cells stably
overexpressing human TLR8 and THP-1 macrophages. Five
compounds inhibited TLR8-mediated signaling, representing a
hit rate of $36\%.$ The three most potent compounds neither
cause cellular toxicity nor inhibition of TLR signaling
induced by other receptor subtypes. Conclusively, we
experimentally confirm novel and selective, pyrimidine-based
TLR8 inhibitors with low cytotoxicity that are relevant
candidates for lead optimization and further mechanistic
studies.},
cin = {EMBL-User},
ddc = {610},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (POF3-622)},
pid = {G:(DE-HGF)POF3-6G3},
experiment = {EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31284084},
UT = {WOS:000486133100055},
doi = {10.1016/j.ejmech.2019.06.084},
url = {https://bib-pubdb1.desy.de/record/430316},
}