College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
Pharmacol Ther. 2012 Mar;133(3):291-8. doi: 10.1016/j.pharmthera.2011.11.001. Epub 2011 Nov 19.
Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, activates the innate immunity system through a receptor complex of myeloid differentiation 2 (MD-2) and toll-like receptor 4 (TLR4). MD-2 directly recognizes the lipid A domain of LPS, which triggers MD-2/TLR4-mediated cellular response aimed at eliminating the invaded pathogen. However, excess production of inflammatory mediators is harmful to host tissue and this can cause septic death in extreme cases. MD-2 represents an attractive therapeutic target of inflammatory and immune diseases in human. In particular, eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site, and it ameliorates various inflammatory conditions due to infection or sterile organ injury. In this review, we outline the recent advances in the structure biology of ligand interaction with MD-2/TLR4, and highlight the MD-2-directed LPS antagonists, which are natural and synthetic chemicals, under development to treat inflammatory diseases.
脂多糖（LPS）是革兰氏阴性菌的内毒素，通过髓样分化因子 2（MD-2）和 Toll 样受体 4（TLR4）受体复合物激活先天免疫系统。MD-2 直接识别 LPS 的脂质 A 结构域，触发 MD-2/TLR4 介导的细胞反应，旨在消除入侵的病原体。然而，炎症介质的过度产生对宿主组织有害，在极端情况下会导致败血症死亡。MD-2 是人类炎症和免疫性疾病的一个有吸引力的治疗靶点。特别是，依罗他滨是一种合成的四酰化脂多糖 A，它直接与 MD-2 结合，并拮抗 LPS 与同一结合位点的结合，它可以改善由于感染或无菌性器官损伤引起的各种炎症状况。在这篇综述中，我们概述了配体与 MD-2/TLR4 相互作用的结构生物学的最新进展，并强调了正在开发的用于治疗炎症性疾病的靶向 MD-2 的 LPS 拮抗剂，包括天然和合成化学物质。
