Generation and in situ evaluation of libraries of poly(acrylic acid) presenting sialosides as side chains as polyvalent inhibitors of influenza-mediated hemagglutination
Generation and in situ evaluation of libraries of poly(acrylic acid) presenting sialosides as side chains as polyvalent inhibitors of influenza-mediated hemagglutination
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DOI：
10.1021/ja963519x
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发表时间：
1997-05-07
影响因子：
15
通讯作者：
Whitesides, GM
中科院分区：
文献类型：
--
作者：
Choi, SK;Mammen, M;Whitesides, GM
本文描述了一种简单、微型的方法，用于生成和评价聚丙烯酸(PAA)的衍生物库，这些库呈现影响其生物活性的侧链混合物。该方法基于聚丙烯酸酐(PAAN)一步转化为侧链上具有多个R单元的线性聚合物PAA(R)：通过超声将PAAN和含水RNH_2的悬浮液超声处理获得，所述悬浮液包含在250亩的L微量滴定板中。用这种方法合成了以N-乙酰神经氨酸(NeuAc-L-NH_2)为侧链的PAA的衍生物PAA(NeuAc-L)，并测定了其抑制甲型流感病毒(X-31)对鸡红细胞凝集的能力；描述这种抑制作用的常数(Khat)是根据NeuAc基团的浓度而不是聚合物分子的浓度来计算的。具有不同摩尔分数范围的GO-聚合PAA(NeuAc-L-n；L-n=不同的连接基团)(CHI(NeuAc-L)=0.02-0.11)表现出K-I(HAI)值在27到0.30mU之间的HAI活性。使用NeuAc-L-NH_2和26种不同伯胺RNH_2的组合，也产生并测定了各种三元聚合物PAA(NeuAc-L；R)(CHI(Neu-Ac-L)类似0.05；chi(R)类似0.06)。某些三元聚合物的K-I(HAI)值比母体共聚PAA(NeuAc-L)的K-I值低约10(4)倍：最活跃的缓蚀剂是PAA(NeuAc-L；L-3-(2‘-萘基)丙氨酸)(K(I)(HAI)约0.05 mM)。通常情况下，疏水侧链的加入增强了活性，尤其是芳香族侧链。这些聚合物(PAA(NeuAc-L；R))属于一类新的聚合物，多价唾液酸苷，能有效地抑制流感病毒吸附到红细胞上。它们是活性的，侧链上只有低到中等水平的官能团掺入：chi(NeuAc-L)类似于0.05；chi(R)类似于0.06。
This paper describes a simple, microscale method for generating and evaluating libraries of derivatives of poly(acrylic acid) (pAA) that present mixtures of side chains that influence their biological activity. The method is based on the one-step conversion of poly(acrylic anhydride) (pAAn) to linear polymers presenting multiple units of R on side chains, pAA(R): the polymers are obtained by ultrasonication of a suspension of pAAn and aqueous RNH2 contained in a 250-mu L well of a microtiter plate. Using this method, derivatives of pAA having N-acetylneuraminic acid (NeuAc-L-NH2) as a side chain, pAA(NeuAc-L), were generated and assayed for ability to inhibit hemagglutination (HAI) of chicken erythrocytes by influenza virus A (X-31); the constant (KHAT) describing this inhibition is calculated on the basis of the concentration of NeuAc groups in solution, rather than the concentration of polymer molecules. Go-polymeric pAA(NeuAc-L-n; L-n=different linking groups) with a range of mole fractions of NeuAc-L-NH2 (chi(NeuAc-L)=0.02-0.11) exhibited HAI activities with K-i(HAI) values between 27 and 0.30 mu M. Using combinations of NeuAc-L-NH2 and one of 26 different primary amines RNH2, a variety of ter-polymeric pAA(NeuAc-L; R) (chi(Neu-Ac-L)similar to 0.05; chi(R) similar to 0.06) were also generated and assayed. Certain ter-polymers yielded values of K-i(HAI) that were lower by a factor of similar to 10(4) than that of the parent co-polymeric pAA(NeuAc-L): the most active inhibitor was pAA(NeuAc-L; L-3-(2'-naphthyl)alanine)) (K(i)(HAI)approximate to 0.05 mM). Typically, the incorporation of hydrophobic-especially aromatic-side chains enhanced activities. These polymers (pAA(NeuAc-L; R)) belong to a new class of polymeric, polyvalent sialosides that are potent inhibitors of the adsorption of influenza virus to erythrocytes. They were active with only low to moderate levels of incorporation of functional groups into the side chains: chi(NeuAc-L)similar to 0.05; chi(R) similar to 0.06.