Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury

作者：Chen, Gaozhi; Zhang, Yali; Liu, Xing; Fang, Qilu; Wang, Zhe; Fu, Lili; Liu, Zhiguo; Wang, Yi; Zhao, Yunjie; Li, Xiaokun; Liang, Guang^*

来源：Journal of Medicinal Chemistry, 2016, 59(6): 2436-2451.

DOI：10.1021/acs.jmedchem.5b01574

• CINNAMIC ACID-DERIVATIVES
• INFLAMMATORY RESPONSE
• LPS BINDING
• PHASE-I
• MD-2
• TARGET
• CURCUMIN
• PATHWAY
• AGENTS
• ANTAGONIST

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.

• 出版日期2016-3-24
• 单位温州医科大学