EFFECTIVE INHIBITORS OF HEMAGGLUTINATION BY INFLUENZA-VIRUS SYNTHESIZED FROM POLYMERS HAVING ACTIVE ESTER GROUPS - INSIGHT INTO MECHANISM OF INHIBITION
EFFECTIVE INHIBITORS OF HEMAGGLUTINATION BY INFLUENZA-VIRUS SYNTHESIZED FROM POLYMERS HAVING ACTIVE ESTER GROUPS - INSIGHT INTO MECHANISM OF INHIBITION
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DOI：
10.1021/jm00021a007
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发表时间：
1995-10-13
影响因子：
7.3
通讯作者：
WHITESIDES, GM
中科院分区：
文献类型：
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作者：
MAMMEN, M;DAHMANN, G;WHITESIDES, GM
使用聚[N-(丙烯酰氧基)琥珀酰亚胺] (pNAS) 合成了高效的含唾液酸的流感病毒 X-31 抑制剂，聚[N-(丙烯酰氧基)琥珀酰亚胺] (pNAS) 是一种通过掺入活性酯基团进行预活化的聚合物。通过 pNAS 分别与两种和三种胺的顺序反应制备含有两种和三种不同组分的聚合物。这种共聚物和三元共聚物的制备方法在合成上比涉及不同单体共聚的方法更有效，并且得到的聚合物比共聚生成的聚合物更容易进行比较。本研究中的聚合物（由单批 pNAS 制备）具有恒定的聚合度（DP 约为 2000），并且可能具有比通过共聚制备的类似聚合物更随机的组分分布。使用唾液酸的 C-糖苷可以在 4 至 36 摄氏度的温度范围内研究不同聚合物的抑制作用，而不会因神经氨酸酶的水解作用而产生假象。一般来说，抑制剂在 36 摄氏度下比在 4 摄氏度下更有效。血凝 (HAI) 测定用于测量每种聚合物的抑制常数 K-i(HAI) 值。在聚丙烯酰胺主链上含有 20% 唾液酸的双组分聚合物在 4℃ 下的 K-i(HAI) 值为 4 nM（就溶液中存在的唾液酸部分而言），并且比之前描述的最佳抑制剂有效大约 50 倍，比最佳天然存在的抑制剂有效 25 倍。这项工作中合成的最有效的抑制剂在聚丙烯酰胺主链上含有 10% 苄胺和 20% 唾液酸，其 K-i(HAI) 值在 36°C 时为 600 pM。分析了大约 100 种在一种或两种成分上不同的聚合物，以区分抑制病毒和红细胞表面相互作用的两种限制机制：通过多价的高亲和力结合和空间稳定。结果表明这两种机制都发挥着重要作用。包含流感引起的红细胞凝集的多价抑制剂的系统提供了可用作其他病原体-宿主相互作用的抑制剂的模型的系统，其中许多病原体-宿主相互作用的抑制剂本身是多价的。
Highly effective sialic acid-containing inhibitors of influenza virus X-31 were synthesized using poly[N-(acryoyloxy)succinimide] (pNAS), a polymer preactivated by incorporation of active ester groups. Polymers containing two and three different components were prepared by sequential reaction of pNAS with two and three amines, respectively. This preparation of co- and terpolymers was synthetically more efficient than methods involving copolymerization of different monomers and gave polymers that were more easily compared than those generated by copolymerization. Polymers in this study (prepared from a single batch of pNAS) had a constant degree of polymerization (DP approximate to 2000) and probably had a distribution of components that was more random than analogous polymers prepared by copolymerization. Use of C-glycosides of sialic acid made it possible to investigate inhibition by different polymers at temperatures ranging from 4 to 36 degrees C without artifacts due to the hydrolytic action of neuraminidase. The inhibitors were, in general, more effective at 36 degrees C than at 4 degrees C. The hemagglutination (HAI) assay was used to measure the value of the inhibition constant K-i(HAI) each polymer. The value of K-i(HAI) for the two-component polymer containing 20% sialic acid on a polyacrylamide backbone at 4 degrees C was 4 nM (in terms of the sialic acid moieties present in solution) and was approximately 50-fold more effective than the best inhibitors previously described and 25-fold more effective than the best naturally occurring inhibitor. The most effective inhibitor synthesized in this work contained 10% benzyl amine and 20% sialic acid on a polyacrylamide backbone, and its value of K-i(HAI) was 600 pM at 36 degrees C. Approximately 100 polymers that differed in one or two components were assayed to distinguish between two limiting mechanisms for inhibition of the interaction between the surfaces of virus and erythrocytes: high-affinity binding through polyvalency, and steric stabilization. The results suggest that both mechanisms play an important role. The system comprising polyvalent inhibitors of agglutination of erythrocytes by influenza provides a system that may be useful as a model for inhibitors of other pathogen-host interactions, a large number of which are themselves polyvalent.