Journal Article

PUBDB-2020-00008

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Identification and characterization of a novel chemotype for human TLR8 inhibitors

Šribar, D. ; Grabowski, M. ; Murgueitio, M. S. ; Bermudez, M. ; Weindl, G. ; Wolber, G.

2019
Elsevier10887 Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ejmech.2019.06.084

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.

Note: © Elsevier Masson SAS. ; Final published version in progress; Post referee fulltext in progress; Embargo 12 months from publication

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; No Fulltext ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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