Department of Bioscience, Graduate School of Science and Technology, Shizuoka University, Shizuoka, Japan.
Bioconjug Chem. 2009 Mar 18;20(3):538-49. doi: 10.1021/bc800460p.
We designed a series of gamma-polyglutamic acid (gamma-PGA)-based glycopolypeptides carrying long/short alpha2,3/6 sialylated glycans to act inhibitors of the influenza virus. As an alternative design, sialoglycopolypeptides carrying long-spacer linked glycans were engineered by replacement of the N-acetyllactosamine (LN) unit by an alkyl chain. The structure-activity relationship of the resulting sialoglycopolypeptides with different glycans in the array has been investigated by in vitro and in vivo infection experiments. The avian viruses specifically bound to glycopolypeptides carrying a short sialoglycan with higher affinity than to a long glycan. In contrast, human viruses, preferentially bound not only to long alpha2,3/6 sialylated glycan with LN repeats in the receptors, but also to more spacer-linked glycan in which the inner sugar has been replaced by a nonsugar structural unit such as a pentylamido group. Taken together, our results indicate that a spaced tandem/triplet pentylamido repeat is a good mimetic of a tandem/triplet LN repeat. Our strategy provides a facile way to design strong polymeric inhibitors of infection by avian and human influenza viruses.
我们设计了一系列基于γ-聚谷氨酸（γ-PGA）的糖肽聚合物，携带长/短α2,3/6 唾液酸化聚糖，作为流感病毒的抑制剂。作为替代设计，通过用烷基链取代 N-乙酰乳糖胺（LN）单元，构建了携带长间隔连接聚糖的唾液糖肽聚合物。通过体外和体内感染实验研究了带有不同聚糖阵列的唾液糖肽聚合物的结构-活性关系。禽病毒特异性地与携带短唾液酸化聚糖的糖肽聚合物结合的亲和力高于与长聚糖的亲和力。相比之下，人类病毒不仅优先结合受体中具有 LN 重复的长α2,3/6 唾液酸化聚糖，而且还结合具有更长间隔连接的聚糖，其中内部糖已被非糖结构单元如戊酰胺基取代。总之，我们的结果表明，间隔串联/三联体戊酰胺基重复是串联/三联体 LN 重复的良好模拟物。我们的策略为设计针对禽和人流感病毒感染的强聚合抑制剂提供了一种简便的方法。
