Abstract
Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co-receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases. In this study, we designed and synthesized 31 chalcone derivatives that contain the moiety of (E)-4-phenylbut-3-en-2-one, which we consider the core structure of current MD2 inhibitors. We first evaluated the anti-inflammatory activities of these compounds in MPMs. For the most active compound 20, we confirmed that it is a specific MD2 inhibitor through a series of biochemical experiments and elucidated that it binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg90 and Tyr102 residues. Compound 20 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-κB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with compound 20 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives we identified is a potential candidate for treating acute inflammatory diseases.
Highlights
Acute lung injury (ALI) is a life-threatening disease characterized by diffuse pulmonary interstitial and alveolar edema that leads to respiratory failure and death[1]
To identify potent analogues with optimal pharmacological properties, we extended the molecular diversity of the chalcone skeleton and synthesized 31 chalcone derivatives (1–31)
The purity was determined by thin-layer chromatography (250 μ silica gel 60 F254 glass plates) and the products were characterized by 1H-NMR, 13C-NMR, HRMS, and ESI-MS
Summary
Acute lung injury (ALI) is a life-threatening disease characterized by diffuse pulmonary interstitial and alveolar edema that leads to respiratory failure and death[1]. TLR4, one of the most extensively researched of these receptors, is responsible for pro-inflammatory activation by LPS12,13. Due to its importance in mediating the interaction between TLR4 and LPS, MD2 has been explored as a therapeutic target for treating acute inflammatory diseases. Chalcone derivatives, xanthohumol and JSH, have been shown to significantly inhibit the LPS-induced TLR4 pathway by antagonizing the binding sites between LPS and MD220,21. Several natural products such as curcumin, caffeic acid phenethyl ester, and 1-dehydro-10-gingerdione have been reported to attenuate the LPS-induced inflammatory response by inhibiting MD222–24. The results suggest that compound 20, a new MD2 inhibitor, has significant potential to be developed as a candidate for treating acute inflammatory diseases
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