Sabesan S, Neira S, Wasserman Z
Central Science and Engineering, Dupont Company, Wilmington, DE 19880-0328.
Carbohydr Res. 1995 Feb 17;267(2):239-61. doi: 10.1016/0008-6215(94)00309-4.
Analogues of the disaccharide alpha-NeuAc-(2-->6)-beta-D-Gal-OR have been made by modifications at C-1 and C-6 of the galactose and at C-4 of the NeuAc unit, for structure-activity relationship studies with influenza virus neuraminidase. These studies indicate that for the influenza neuraminidase, a larger aglycon at C-1 of galactose is less preferred, whereas the restriction of the rotamer orientation at C-6 of galactose in the "tg" mode favors enzyme binding. Substitution at C-4 of the NeuAc unit has the most profound effect in the influenza neuraminidase hydrolysis and inhibition. For example, azido and acetamido groups at C-4 of the NeuAc units render the sialosides resistant to neuraminidase hydrolysis. However, these derivatives are not inhibitors of the neuraminidase, indicating their lack of binding. On the other hand, a 4-amino substitution of the NeuAc unit not only renders the corresponding sialosides neuraminidase-resistant, but also makes them potent neuraminidase inhibitors. This potent inhibition indicates that the 4-amino groups in these sialosides may engage in favorable interaction with amino acids at the neuraminidase active-site. The conclusion is also supported by docking studies of the carbohydrate structures at the neuraminidase active-site.
通过对半乳糖的C-1和C-6以及NeuAc单元的C-4进行修饰，制备了二糖α-NeuAc-(2→6)-β-D-半乳糖-OR的类似物，用于流感病毒神经氨酸酶的构效关系研究。这些研究表明，对于流感神经氨酸酶而言，半乳糖C-1位上较大的糖苷配基不太受青睐，而半乳糖C-6位上“tg”模式下旋转异构体取向的限制有利于酶的结合。NeuAc单元C-4位的取代对流感神经氨酸酶的水解和抑制作用影响最为显著。例如，NeuAc单元C-4位上的叠氮基和乙酰氨基使唾液酸苷对神经氨酸酶水解具有抗性。然而，这些衍生物不是神经氨酸酶的抑制剂，表明它们缺乏结合能力。另一方面，NeuAc单元的4-氨基取代不仅使相应的唾液酸苷对神经氨酸酶具有抗性，还使其成为有效的神经氨酸酶抑制剂。这种强效抑制表明这些唾液酸苷中的4-氨基可能与神经氨酸酶活性位点的氨基酸发生有利的相互作用。碳水化合物结构在神经氨酸酶活性位点的对接研究也支持了这一结论。
