Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury.
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 Arg(90) and Tyr(102) 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.
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Yali
Y
Zhang
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Jianzhang
J
Wu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Shilong
S
Ying
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Gaozhi
G
Chen
The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Beibei
B
Wu
The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Tingting
T
Xu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Zhiguo
Z
Liu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Xing
X
Liu
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Lehao
L
Huang
The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Xiaoou
X
Shan
The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Yuanrong
Y
Dai
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Guang
G
Liang
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D002599:Chalcone / Q000031:analogs & derivatives; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006860:Hydrogen Bonding; D008070:Lipopolysaccharides / Q000009:adverse effects; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D051381:Rats
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D002599:Chalcone