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DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY · 2021 · IF 3.636

TLR1 in Nile tilapia: The conserved receptor cannot interact with MyD88 and TIRAP but can activate NF-κB in vitro

Feng-Ying Gao,Xin Zhou,Mai-Xin Lu,Miao Wang,Zhi-Gang Liu,Jian-Meng Cao,Xiao-Li Ke,Meng-Meng Yi,Deng-Gao Qiu

Toll-like receptors (TLRs) play a critical role in the innate immune response of fish. In this study, we isolated the cDNA sequence of Nile tilapia TLR1 ( On TLR1). The deduced OnTLR1 protein contains a signal peptide , 7 leucine-rich repeats (LRRs), a C-terminal LRR (LRR-CT), a transmembrane region and a highly conserved TIR domain. In healthy Nile tilapia, the On TLR1 transcript was broadly expressed in all examined tissues, with the highest expression levels in the spleen . After infection with Streptococcus agalactiae , the On TLR1 transcripts were upregulated in the gill and kidney. After stimulation with polyinosinic-polycytidylic acid (poly(I:C)), the expression levels of On TLR1 were significantly downregulated in the intestine , whereas On TLR1 transcripts were significantly upregulated in the kidney. After challenge with lipopolysaccharide (LPS), the expression levels of On TLR1 were significantly upregulated in the spleen and kidney. The subcellular localization showed that On TLR1 was expressed in the cytoplasm. TLR1 significantly increased MyD88-dependent NF-κB activity. However, the results of a pull-down assay showed that On TLR1 did not interact with MyD88 or TIRAP. Binding assays revealed the specificity of OnTLR1 for pathogen-associated molecular patterns (PAMPs) and bacteria that included S. agalactiae , Aeromonas hydrophila and poly(I:C) and LPS. Taken together, these findings suggest that OnTLR1, as a pattern recognition receptor (PRR), might play an important role in the immune response to pathogen invasion.

研究领域: 免疫学 · 分子生物学 · 鱼类生物学 · 病原识别

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JOURNAL OF MEDICINAL CHEMISTRY · 2025 · IF 6.8

Design, Synthesis, and Structure–Activity Relationship of Novel Human TLR1/2 Agonists for Potential Immunotherapy

Qiuyue Fu,Yue Pan,Peixi Wu,Zhuoxian Cao,Liu Shi,Lan Huang,Kui Cheng,Zhipeng Chen

Capitalizing on the advantages of Toll-like receptor 2 (TLR2) small-molecule agonists combining high potency and low toxicity in cancer therapy, we designed and synthesized a novel series of thiourea-based TLR2 small-molecule agonists and identified a low-toxicity TLR1/2-specific small molecule agonist SMU-C409 (EC50 = 65 ± 3 nM). SMU-C409 incorporates key optimizations: a carbonyl conservation strategy eliminates carboxylesterase-mediated degradation, and a quinoline (N-heterocycle) enables salt formation that boosts solubility by 3.4-fold (free base) and 5.5-fold (hydrochloride) relative to the lead compound SMU-C80 (EC50 = 43 ± 5 nM), while retaining potent agonistic activity and exhibiting superior plasma stability, which is critical for favorable pharmacokinetics and efficacy. Mechanistically, SMU-C409 activates TLR1/2, recruits MyD88, induces NF-κB phosphorylation, and stimulates TNF-α/IL-1β secretion; in vitro studies confirm robust immune cell activation and antitumor immunomodulation. SMU-C409 overcomes core limitations of TLR2 agonists while maintaining high potency, positioning it as a promising candidate for advancing cancer immunotherapy.

研究领域: 免疫学 · 药物化学 · 癌症免疫治疗 · 分子药理学 · 药物设计与开发

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JOURNAL OF MEDICINAL CHEMISTRY · 2021 · IF 7.446

Design, Synthesis, and Structure–Activity Relationship of N-Aryl-N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy

Zhipeng Chen,Lina Zhang,Junjie Yang,Lu Zheng,Fanjie Hu,Siqin Duan,Kutty Selva Nandakumar,Shuwen Liu,Hang Yin,Kui Cheng

The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.

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TLR1 in Nile tilapia: The conserved receptor cannot interact with MyD88 and TIRAP but can activate NF-κB in vitro

Design, Synthesis, and Structure–Activity Relationship of Novel Human TLR1/2 Agonists for Potential Immunotherapy

Design, Synthesis, and Structure–Activity Relationship of N-Aryl-N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy