Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury
Discovery of a New Inhibitor of Myeloid Differentiation 2 from Cinnamamide Derivatives with Anti-Inflammatory Activity in Sepsis and Acute Lung Injury
复制标题
从肉桂酰胺衍生物中发现一种新的骨髓分化抑制剂 2，在脓毒症和急性肺损伤中具有抗炎活性
DOI：
10.1021/acs.jmedchem.5b01574
复制
发表时间：
2016-03-24
影响因子：
7.3
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Gaozhi;Zhang, Yali;Liang, Guang
急性炎症性疾病，包括急性肺损伤和脓毒症，仍然是全球重症监护病房中最常见的危及生命的疾病。肉桂酰胺已被纳入几种具有治疗潜力的合成化合物，包括抗炎特性。然而，肉桂酰胺类化合物抗炎作用的可能机制和直接的分子靶点研究较少。本研究合成了一系列肉桂酰胺类化合物，并对其抗炎活性进行了评价。发现最具活性的化合物2 i在体外阻断LPS诱导的MD 2/TLR 4促炎信号传导激活，并在体内减轻LPS引起的脓毒症和急性肺损伤。从机制上讲，我们证明了2 i通过直接靶向和结合Arg 90和Tyr 102残基中的MD 2并抑制MD 2/TLR 4复合物的形成来发挥其抗炎作用。总之，这项工作提出了一种新的MD 2抑制剂，2 i，它有可能被开发为治疗脓毒症的候选药物，并为开发靶向MD 2的抗炎药提供了一个新的先导结构。
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.