Pritchett T J, Paulson J C
Department of Biological Chemistry, UCLA School of Medicine 90024.
J Biol Chem. 1989 Jun 15;264(17):9850-8.
The unique properties of equine and guinea pig sera which make them potent inhibitors of influenza virus adsorption and infection have been investigated. The inhibitory activities of both sera are found to reside entirely in their respective alpha 2-macroglobulins, high molecular weight glycoproteins which bind to viral hemagglutinins via sialic acids of their N-linked carbohydrate groups. Structure analysis has shown that both proteins contain 4-O-acetyl-N-acetylneuraminic acid (4-O-Ac-NeuAc) (Hanaoka, K., Pritchett, T. J., Takasaki, S., Kochibe, N., Sabesan, S., Paulson, J.C., and Kobata, A. (1989) J. Biol. Chem. 264, 9842-9849). These 4-O-acetylated sialic acids have been found in few species, making their coincidence with high inhibitory potency in equine and guinea pig alpha 2-macroglobulin striking. However, 4-O-Ac-NeuAc does not appear to increase the avidity of interaction with influenza virus since isolated oligosaccharides of equine alpha 2-macroglobulin are no more potent inhibitors of adsorption than isolated oligosaccharides of human alpha 2-macroglobulin, which is a relatively poor inhibitor and contains only NeuAc. Since 4-O-Ac-NeuAc is resistant to cleavage by viral sialidase it may serve to protect the inhibitor from inactivation. These and supporting results suggest that the key property of equine and guinea pig alpha 2-macroglobulin which make them high potency inhibitors is a spatial arrangement of sialic acid containing oligosaccharide groups which allows optimal interaction with multiple hemagglutinins. The implications of these results for the design of low molecular weight inhibitors of influenza virus infection are discussed.
对马血清和豚鼠血清的独特特性进行了研究，这些特性使它们成为流感病毒吸附和感染的有效抑制剂。发现两种血清的抑制活性完全存在于各自的α2-巨球蛋白中，α2-巨球蛋白是一种高分子量糖蛋白，通过其N-连接碳水化合物基团的唾液酸与病毒血凝素结合。结构分析表明，两种蛋白质都含有4-O-乙酰基-N-乙酰神经氨酸（4-O-Ac-NeuAc）（花冈，K.，普里切特，T.J.，高崎，S.，小池部，N.，萨贝桑，S.，保尔森，J.C.，和小幡，A.（1989年）《生物化学杂志》264，9842-9849）。这些4-O-乙酰化唾液酸在少数物种中被发现，它们与马和豚鼠α2-巨球蛋白中的高抑制效力同时出现令人惊讶。然而，4-O-Ac-NeuAc似乎并没有增加与流感病毒相互作用的亲和力，因为马α2-巨球蛋白的分离寡糖并不比人α2-巨球蛋白的分离寡糖更有效地抑制吸附，人α2-巨球蛋白是一种相对较差的抑制剂，只含有NeuAc。由于4-O-Ac-NeuAc对病毒唾液酸酶的切割具有抗性，它可能有助于保护抑制剂不被灭活。这些及相关结果表明，马和豚鼠α2-巨球蛋白成为高效抑制剂的关键特性是含唾液酸寡糖基团的空间排列，这种排列允许与多种血凝素进行最佳相互作用。讨论了这些结果对设计流感病毒感染的低分子量抑制剂的意义。
