Fantini Jacques
Université Paul Cézanne, Laboratoire des Interactions Moléculaires et Systèmes Membranaires, Faculté des Sciences et Techniques de Saint-Jérôme, Service 331, 13397 Marseille Cedex 20, France.
Curr Med Chem. 2007;14(27):2911-7. doi: 10.2174/092986707782360033.
The wide biochemical diversity of glycolipids in membranes explains why these molecules are often selected by pathogens (viruses, bacteria, prions) as primary sites of interactions with the cell surface. Moreover, glycolipids concentrate into cholesterol/glycolipid-rich microdomains where they can reach high local concentrations consistent with the multivalent attachment of pathogens on the cell surface. Finally, recent studies have shown that glycolipids could also modulate protein conformation. This chaperone activity of glycolipids has been associated with various pathogenic processes including HIV infection, prion propagation, and amyloid aggregation in Alzheimer's and Creutzfeldt-Jakob's diseases. Despite the potential interest for drugs mimicking glycolipid structure and function, the physicochemical properties of authentic glycolipids suggested that it might be difficult to obtain synthetic glycolipid analogues able to neutralise those pathogens before they could reach the cell surface. Recent data obtained with mono-, di-, and tri-hexosylceramide (GalCer, LacCer and Gb(3)) have proven that this was absolutely not the case and that highly active inhibitors could be designed through slight modifications of glycolipid structure. Biochemical studies of glycolipid-protein interactions have highlighted the importance of CH-pi stacking interactions between galactosyl head groups of the glycolipid and aromatic amino acids of the protein. The discovery of this unique mechanism of interaction may allow a rational strategy for the design and synthesis of glycolipid-based molecules as new anti-infectious and/or anti-amyloidogenesis compounds. This strategy, which takes into account the hierarchical organisation of glycolipids into discrete membrane microdomains as well as their association with cholesterol, is discussed in the present review.
膜中糖脂广泛的生化多样性解释了为什么这些分子常常被病原体（病毒、细菌、朊病毒）选为与细胞表面相互作用的主要位点。此外，糖脂会聚集到富含胆固醇/糖脂的微结构域中，在那里它们能够达到与病原体在细胞表面的多价附着相一致的高局部浓度。最后，最近的研究表明糖脂还可以调节蛋白质构象。糖脂的这种伴侣活性与包括HIV感染、朊病毒传播以及阿尔茨海默病和克雅氏病中的淀粉样蛋白聚集等各种致病过程相关。尽管模拟糖脂结构和功能的药物具有潜在的研究价值，但天然糖脂的物理化学性质表明，要获得能够在病原体到达细胞表面之前中和它们的合成糖脂类似物可能很困难。最近使用单、二和三己糖神经酰胺（半乳糖神经酰胺、乳糖神经酰胺和Gb(3)）获得的数据证明情况并非如此，并且通过对糖脂结构进行轻微修饰可以设计出高活性抑制剂。糖脂 - 蛋白质相互作用的生化研究突出了糖脂的半乳糖基头部基团与蛋白质的芳香族氨基酸之间CH-π堆积相互作用的重要性。这种独特相互作用机制的发现可能为设计和合成基于糖脂的分子作为新型抗感染和/或抗淀粉样蛋白生成化合物提供一种合理策略。本综述讨论了这种策略，该策略考虑了糖脂在离散膜微结构域中的分层组织以及它们与胆固醇的关联。
