Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1-imidazo[4,5-]quinolin-4-amine led to the identification of a potent hTLR7-specific -hydroxymethyl IMDQ with an EC value of 0.22 μM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide with EC values of 0.32 μM for hTLR7 and 18.25 μM for hTLR8. In the vaccination study, TLR7-specific compound alone or combined with alum (aluminum hydroxide wet gel) showed adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the adjuvant system comprising carboxamide and alum showed prominent adjuvant activity with high levels of IgG1, IgG2b, and IgG2c in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine adjuvant.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c00464 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Systematic assessment of COVID-19 host genetics using whole genome sequencing data.
PLoS Pathog
December 2024
Institute of Human Genetics, School of Medicine, University Bonn & University Hospital Bonn, Bonn, Germany.
Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.
View Article and Find Full Text PDFAmodiaquine Analogs Are Potent Inhibitors of Interleukin-6 Production Induced by Activation of Toll-Like Receptors Recognizing Pathogen Nucleic Acids.
Biol Pharm Bull
December 2024
Department of Radiation Biosciences, Graduate School of Pharmaceutical Sciences, Tokyo University of Science.
Excessive inflammatory responses to viral infections, known as cytokine storms, are caused by overactivation of endolysosomal Toll-like receptors (TLRs) (TLR3, TLR7, TLR8, and TLR9) and can be lethal, but no specific treatment is available. Some quinoline derivatives with antiviral activity were tried during the recent coronavirus disease 2019 (COVID-19) pandemic, but showed serious toxicity, and their efficacy for treating viral cytokine storms was not established. Here, in order to discover a low-toxicity quinoline derivative as a candidate for controlling virally induced inflammation, we synthesized a series of derivatives of amodiaquine (ADQ), a quinoline approved as an antimalarial, and tested their effects on TLRs-mediated production of inflammatory cytokines and cell viability in vitro.
View Article and Find Full Text PDFPPS-TLR7/8 agonist nanoparticles equip robust anticancer immunity by selectively prolonged activation of dendritic cells.
Biomaterials
May 2025
Wuya college of innovation, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang, 110016, China; Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China. Electronic address:
Checkpoint inhibitor therapies do not benefit all patients, and adjuvants play a critical role in boosting immune responses for effective cancer immunotherapy. However, their systemic toxicity and suboptimal activation kinetics pose significant challenges. Here, this study presented a linker-based strategy to modulate the activation kinetics of Toll-like receptor 7/8 (TLR7/8) agonists delivered via poly (propylene sulfide) nanoparticles (PPS NPs).
View Article and Find Full Text PDFTargeting toll-like receptor 7 as a therapeutic development strategy for systemic lupus erythematosus.
Acta Pharm Sin B
November 2024
State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.
Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism.
View Article and Find Full Text PDFThe effect of toll-like receptor 7/8 ligand in inhibiting the motility of putative X-chromosome-bearing sperm in rams.
J Adv Vet Anim Res
September 2024
Department of Animal Production, Faculty of Animal Husbandry, Universitas Padjadjaran, Bandung, West Java, Indonesia.
Objectives: This study aims to determine the effect of a toll-like receptor 7/8 (TLR7/8) ligand on the motility of putative X- and Y-chromosome-bearing sperm in rams.
Materials And Methods: Sperm from three fertile rams were incubated with tris-citrate buffer containing 0 to 0.9 μM resiquimod (a TLR7/8 ligand) that affects only the X chromosome sperm.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!