Disaccharide-Based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-Induced Inflammation
Disaccharide-Based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide-Induced Inflammation
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DOI：
10.1002/cmdc.201800505
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发表时间：
2018-11-06
期刊：
影响因子：
3.4
通讯作者：
Zamyatina, Alla
中科院分区：
文献类型：
--
作者：
Borio, Alessio;Holgado, Aurora;Zamyatina, Alla
尽管在过去十年中在理解脓毒症的分子机制和开发临床相关疗法方面取得了重大进展，但脓毒症仍然是重症监护室死亡的主要原因，全球范围内的发病率不断增加。Toll样受体4（TLR 4）是一种跨膜模式识别受体，负责传播对革兰氏阴性细菌感染的即时免疫应答，在脓毒症和慢性炎症相关疾病的发病机制中起着重要作用。TLR 4与脂多糖（LPS）敏感蛋白髓样分化-2（MD-2）复合，其代表用于建立新的抗炎治疗策略的优选靶标。在此，我们报告了新的基于dislidamide的TLR 4-MD-2拮抗剂的开发、简易合成和生物学评价，其在微摩尔浓度下具有有效的抗内毒素活性。一系列的合成阴离子糖脂需要酰胺连接的β-酮酰基脂质残基的制备在一个简单的方式，通过使用一个单一的正交保护的非还原二葡糖胺支架。在人免疫细胞（MNC和THP 1）和小鼠巨噬细胞中监测并证实了对LPS诱导的白细胞介素-6和肿瘤坏死因子释放的抑制。结构-活性关系研究和分子动力学模拟揭示了阴离子糖脂和MD-2之间高亲和力相互作用的结构基础，并强调了两种化合物作为潜在抗炎治疗药物开发的先导。
Despite significant advances made in the last decade in the understanding of molecular mechanisms of sepsis and in the development of clinically relevant therapies, sepsis remains the leading cause of mortality in intensive care units with increasing incidence worldwide. Toll-like receptor 4 (TLR4)-a transmembrane pattern-recognition receptor responsible for propagating the immediate immune response to Gram-negative bacterial infection-plays a central role in the pathogenesis of sepsis and chronic inflammation-related disorders. TLR4 is complexed with the lipopolysaccharide (LPS)-sensing protein myeloid differentiation-2 (MD-2) which represents a preferred target for establishing new anti-inflammatory treatment strategies. Herein we report the development, facile synthesis, and biological evaluation of novel disaccharide-based TLR4-MD-2 antagonists with potent anti-endotoxic activity at micromolar concentrations. A series of synthetic anionic glycolipids entailing amide-linked beta-ketoacyl lipid residues was prepared in a straightforward manner by using a single orthogonally protected nonreducing diglucosamine scaffold. Suppression of the LPS-induced release of interleukin-6 and tumor necrosis factor was monitored and confirmed in human immune cells (MNC and THP1) and mouse macrophages. Structure-activity relationship studies and molecular dynamics simulations revealed the structural basis for the high-affinity interaction between anionic glycolipids and MD-2, and highlighted two compounds as leads for the development of potential anti-inflammatory therapeutics.