Identification and validation of a novel dual small-molecule TLR2/8 antagonist.
Benzothiazoles
/ chemistry
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Interleukin-8
/ metabolism
Macrophages
/ cytology
Molecular Structure
Protein Multimerization
/ drug effects
Signal Transduction
/ drug effects
Small Molecule Libraries
/ chemistry
THP-1 Cells
Toll-Like Receptor 2
/ antagonists & inhibitors
Toll-Like Receptor 8
/ antagonists & inhibitors
Computer modeling
Drug discovery
Dual antagonist
Inflammation
Innate immunity
Non-competitive antagonism
Toll-like receptor (TLR)
Virtual screening
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
15
02
2020
accepted:
01
04
2020
pubmed:
9
4
2020
medline:
29
12
2020
entrez:
9
4
2020
Statut:
ppublish
Résumé
Toll-like receptor 2 (TLR2) and TLR8 are involved in the recognition of bacterial and viral components and are linked not only to protective antimicrobial immunity but also to inflammatory diseases. Recently, increasing attention has been paid to the receptor crosstalk between TLR2 and TLR8 to fine-tune innate immune responses. In this study, we report a novel dual TLR2/TLR8 antagonist, compound 24 that was developed by a modeling-guided synthesis approach. The modulator was optimized from the previously reported 1,3-benzothiazole derivative, compound 8. Compound 24 was pharmacologically characterized for the ability to inhibit TLR2- and TLR8-mediated responses in TLR-overexpressing reporter cells and THP-1 macrophages. The modulator showed high efficacy with IC
Identifiants
pubmed: 32268138
pii: S0006-2952(20)30185-4
doi: 10.1016/j.bcp.2020.113957
pii:
doi:
Substances chimiques
Benzothiazoles
0
Interleukin-8
0
Small Molecule Libraries
0
Toll-Like Receptor 2
0
Toll-Like Receptor 8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113957Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.