Optimization and anti-inflammatory evaluation of methyl gallate derivatives as a myeloid differentiation protein 2 inhibitor.

Abstract

Myeloid differentiation protein 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) responsible for the recognition of lipopolysaccharide (LPS) and mediates a series of TLR4-dependent inflammatory responses in inflammatory lung diseases including acute lung injury (ALI). Targeting MD2 thus may provide a therapeutic strategy against these lung diseases. In this study, we identified a novel compound 4k with the potent anti-inflammatory activity among 39 methyl gallate derivatives (MGDs). MGD 4k exhibited a high binding affinity to MD2, which in turn prevented the formation of the LPS/MD2/TLR4 complex. In addition, MGD 4k significantly reversed the upregulation of LPS-induced inflammatory mediators such as tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 in vitro and in vivo. Mechanistically, MGD 4k performed anti-inflammatory function by inactivating JNK, ERK and p38 signaling pathways. Taken together, our study identified MGD 4k as a novel potential therapeutic agent for ALI through inhibiting MD2, inflammatory responses, and major inflammation-associated signaling pathways.

• Authors: Yinda Qiu, Zhongxiang Xiao, Yanyan Wang, Dingfang Zhang, Wenxin Zhang, Guangbao Wang, Wenbin Chen, Guang Liang, Xiaokun Li, Yali Zhang, Zhiguo Liu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 27 Issue 20 Pg. 115049 (10 15 2019) ISSN: 1464-3391 [Electronic] England
• PMID: 31466835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Lipopolysaccharides
• Ly96 protein, mouse
• Lymphocyte Antigen 96
• methyl gallate
• Gallic Acid

Topics

• Acute Lung Injury (chemically induced, drug therapy, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Bronchoalveolar Lavage Fluid (chemistry)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Gallic Acid (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Lymphocyte Antigen 96 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Structure-Activity Relationship