2. Academic Validation
  3. Discovery of novel TLR2 antagonists as anti-inflammatory agents

Discovery of novel TLR2 antagonists as anti-inflammatory agents

  • Bioorg Chem. 2025 Jul 30:164:108805. doi: 10.1016/j.bioorg.2025.108805.
Xuehang Tang 1,  Luyao Qi 2,  Yingxia Li 3,  Wei Tang 4,  Wei Zhang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: tangwei@simm.ac.cn.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: zhangw416@fudan.edu.cn.
PMID: 40774108 DOI: 10.1016/j.bioorg.2025.108805
Abstract

Toll-like receptors (TLRs) were the first identified Pattern Recognition Receptors of the innate immune system. In TLRs family, Toll-like Receptor 2 (TLR2) is notable for its extensive expression across various tissues and its ability to recognize a diverse array of pathogenic Microorganisms and their products. However, long term or excessive activation of TLR2 can lead to inflammatory, autoimmune disorders and neurodegenerative diseases. Modulation of TLR2 function by small molecules is considered as a promising strategy for the treatment of these diseases. Among the reported TLR2 antagonists, MMG-11, as a selective TLR2 Antagonist with low cytotoxicity, can effectively inhibit excessive TLR2 activation and the production of inflammatory factors. However, MMG-11 contained the pyrogallol fragment which reduces the metabolic stability and synthetic accessibility. Meanwhile, the biological activity of MMG-11 needs to be further improved. Herein we designed and synthesized a series of TLR2 antagonists starting from MMG-11 for improving antagonistic activity and metabolic stability. Among thirty tested compounds, T30 exhibited better inhibitory activity and metabolic stability than MMG-11 (T30 IC50 = 11.41 ± 0.83 μM vs MMG-11 IC50 = 22.58 ± 0.97 μM; T30 T1/2 = 16.67 min vs MMG-11 T1/2 = 7.88 min). T30 also showed reasonable toxicity profiles and deserved further research.

Keywords

Anti-inflammatory; Structure–activity relationship; TLR2 antagonists; Toll-like receptor 2.

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