Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury
Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury
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发现咖啡酸苯乙酯衍生物作为新型骨髓分化蛋白 2 抑制剂治疗急性肺损伤
DOI：
10.1016/j.ejmech.2017.11.066
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Lingfeng;Jin, Yiyi;Liang, Guang
髓样分化蛋白2（MD 2）是识别脂多糖（LPS）的重要分子，通过激活Toll样受体4（TLR 4）信号传导导致炎症的起始。来自蜂箱蜂胶的咖啡酸苯乙酯（CAPE）可以干扰LPS与TLR 4/MD 2复合物之间的相互作用，从而具有很有前途的抗炎特性。本研究设计并合成了48个CAPE衍生物，并在LPS激活的小鼠原代腹腔巨噬细胞（MPM）中评价了它们的抗炎活性。发现最具活性的化合物10 s以高亲和力与MD 2结合，这阻止了LPS/MD 2/TLR 4复合物的形成。10 s的结合模式表明，与MD 2的主要相互作用建立通过两个关键的氢键和疏水相互作用。此外，10 s对LPS引起的急性肺损伤（ALI）有明显的保护作用。总之，这项工作提供了新的铅结构和候选人作为MD 2抑制剂的抗炎药物的发展。(C)2017 Elsevier Masson SAS。All rights reserved.
Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs. (C) 2017 Elsevier Masson SAS. All rights reserved.