2. Academic Validation
  3. Eupalinolide B inhibits periodontitis development by targeting ubiquitin conjugating enzyme UBE2D3

Eupalinolide B inhibits periodontitis development by targeting ubiquitin conjugating enzyme UBE2D3

  • MedComm (2020). 2025 Jan 14;6(1):e70034. doi: 10.1002/mco2.70034.
Wenhua Kuang 1,  Ruishen Zhuge 1 2,  Ping Song 1 3,  Letai Yi 1 4,  Shujie Zhang 5,  Ying Zhang 5,  Yin Kwan Wong 1,  Ruixing Chen 6,  Junzhe Zhang 5,  Yuanbo Wang 2,  Dandan Liu 5,  Zipeng Gong 1 6,  Peili Wang 1 3,  Xiangying Ouyang 1 2,  Jigang Wang 1 5 7
Affiliations

Affiliations

  • 1 Department of Urology, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology Shenzhen China.
  • 2 Department of Periodontology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology Beijing China.
  • 3 National Clinical Research Center for Chinese Medicine Cardiology Xiyuan Hospital, China Academy of Chinese Medical Sciences Beijing China.
  • 4 Inner Mongolia Medical University Hohhot China.
  • 5 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences Beijing China.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics Guizhou Medical University Guiyang China.
  • 7 State Key Laboratory of Antiviral Drugs, School of Pharmacy Henan University Kaifeng China.
PMID: 39811801 DOI: 10.1002/mco2.70034
Abstract

Periodontitis is a chronic periodontal inflammatory disease caused by periodontal pathogens commonly seen in adults. Eupalinolide B (EB) is a sesquiterpenoid natural product extracted from Eupatorium lindleyanum and has been reported as a potential drug for cancers and immune disorders. Here, we explored the ameliorative effects and underlying molecular mechanism of EB on periodontitis for the first time. We demonstrated that EB ameliorates periodontal inflammation and alveolar bone resorption with a ligated periodontitis mouse model. In addition, the impact of EB on macrophages inflammation was examined in the Raw264.7 cell line. We identified ubiquitin-conjugating enzyme, UBE2D3, as the direct covalent binding protein targets of EB by using a chemoproteomic method based on activity-based protein profiling, biolayer interferometry method, and cellular thermal shift assay. Furthermore, the direct binding site of EB to UBE2D3 was identified using high-resolution mass spectrometry and confirmed by experiments. Taken together, EB ameliorates periodontitis by targeting UBE2D3 to suppress the ubiquitination degradation of IκBα, leading to inactivation of nuclear transcription factor-κB signaling pathway. And this was confirmed by siRNA-mediated gene knockdown in inflammatory macrophages. Our results suggested that EB may be a new kind of UBE2D3 inhibitor and may become a promising therapeutic agent for anti-periodontitis.

Keywords

chemical biology; drug targets; natural product; proteomics; target identification.

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