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Discovery of Novel Small Molecule Dual Inhibitor Targeting Toll-Like Receptors 7 and 9
  • Haseeb, Muhammad ;
  • Choi, Yang Seon ;
  • Patra, Mahesh Chandra ;
  • Jeong, Uisuk ;
  • Lee, Wang Hee ;
  • Qayyum, Naila ;
  • Choi, Hongjoon ;
  • Kim, Wook ;
  • Choi, Sangdun
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Publication Year
2024-07-08
Journal
Journal of Chemical Information and Modeling
Publisher
American Chemical Society
Citation
Journal of Chemical Information and Modeling, Vol.64 No.13, pp.5090-5107
Mesh Keyword
Cell-beCell/B.EDendriticsDual inhibitorsImmune cellsInhibitory compoundsMitogen-activated protein kinaseProinflammatory cytokinesSmall moleculesToll-like receptorsAnimalsDrug DiscoveryHumansMiceMolecular Docking SimulationSignal TransductionSmall Molecule LibrariesToll-Like Receptor 7Toll-Like Receptor 9Tumor Necrosis Factor-alpha
All Science Classification Codes (ASJC)
Chemistry (all)Chemical Engineering (all)Computer Science ApplicationsLibrary and Information Sciences
Abstract
The aberrant secretion of proinflammatory cytokines by immune cells is the principal cause of inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Toll-like receptor 7 (TLR7) and TLR9, sequestered to the endosomal compartment of dendritic cells and macrophages, are closely associated with the initiation and progression of these diseases. Therefore, the development of drugs targeting dysregulated endosomal TLRs is imperative to mitigate systemic inflammation. Here, we applied the principles of computer-aided drug discovery to identify a novel low-molecular-weight compound, TLR inhibitory compound 10 (TIC10), and its potent derivative (TIC10g), which demonstrated dual inhibition of TLR7 and TLR9 signaling pathways. Compared to TIC10, TIC10g exhibited a more pronounced inhibition of the TLR7- and TLR9-mediated secretion of the proinflammatory cytokine tumor necrosis factor-α in a mouse macrophage cell line and mouse bone marrow dendritic cells in a concentration-dependent manner. While TIC10g slightly prevented TLR3 and TLR8 activation, it had no impact on cell surface TLRs (TLR1/2, TLR2/6, TLR4, or TLR5), indicating its selectivity for TLR7 and TLR9. Additionally, mechanistic studies suggested that TIC10g interfered with TLR9 activation by CpG DNA and suppressed downstream pathways by directly binding to TLR9. Western blot analysis revealed that TIC10g downregulated the phosphorylation of the p65 subunit of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase, p38-MAPK, and c-Jun N-terminal kinase. These findings indicate that the novel ligand, TIC10g, is a specific dual inhibitor of endosomal TLRs (TLR7 and TLR9), disrupting MAPK- and NF-κB-mediated proinflammatory gene expression.
ISSN
1549-960X
Language
eng
URI
https://aurora.ajou.ac.kr/handle/2018.oak/34293
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85196941010&origin=inward
DOI
https://doi.org/10.1021/acs.jcim.4c00578
Journal URL
http://pubs.acs.org/journal/jcisd8
Type
Article
Funding
The present study received financial support from various sources, including the Korea Drug Development Fund, which is funded by the Ministry of Science and ICT, the Ministry of Trade, Industry, and Energy, and the Ministry of Health and Welfare (HN21C1058). The National Research Foundation of Korea also provided financial support through the following grants: NRF-2022M3A9G1014520, 2023R1A2C2003034, 2019M3D1A1078940, and 2019R1A6A1A11051471.
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College of Bio-convergence Engineering
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