ArticleJournal of medicinal chemistry2013
Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 80 citations in OpenAlex.
- Review
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- Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation.Bioorganic & medicinal chemistry · 2021Article
- Receptor-Ligand Kinetics Influence the Mechanism of Action of Covalently Linked TLR Ligands.ACS chemical biology · 2021Article
- Subunit Vaccines Using TLR Triagonist Combination Adjuvants Provide Protection AgainstFrontiers in immunology · 2021Article
- Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics.Acta pharmacologica Sinica · 2020Review
- Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes.Frontiers in pharmacology · 2020Article
- Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview.Frontiers in immunology · 2020Review
- A Novel Synthetic Dual Agonistic Liposomal TLR4/7 Adjuvant Promotes Broad Immune Responses in an Influenza Vaccine With Minimal Reactogenicity.Frontiers in immunology · 2020Article
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.