title: Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury.
abstract: Acute inflammatory diseases, including acute lung injury and sepsis, remain the most common life-threatening illness in intensive care units worldwide. Cinnamamide has been incorporated in several synthetic compounds with therapeutic potentials including anti-inflammatory properties. However, the possible mechanism and direct molecular target of cinnamamides for their anti-inflammatory effects were rarely investigated. In this study, we synthesized a series of cinnamamides and evaluated their anti-inflammatory activities. The most active compound, 2i, was found to block LPS-induced MD2/TLR4 pro-inflammatory signaling activation in vitro and to attenuate LPS-caused sepsis and acute lung injury in vivo. Mechanistically, we demonstrated that 2i exerts its anti-inflammatory effects by directly targeting and binding MD2 in Arg90 and Tyr102 residues and inhibiting MD2/TLR4 complex formation. Taken together, this work presents a novel MD2 inhibitor, 2i, which has the potential to be developed as a candidate for the treatment of sepsis, and provides a new lead structure for the development of anti-inflammatory agents targeting MD2.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Gaozhi
authors.initials: G
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Qilu
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Fu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D055808:Drug Discovery; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D000067996:RAW 264.7 Cells; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy*; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002934:Cinnamates; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C411088:cinnamamide