Reuter J D, Myc A, Hayes M M, Gan Z, Roy R, Qin D, Yin R, Piehler L T, Esfand R, Tomalia D A, Baker J R
Center for Biologic Nanotechnology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bioconjug Chem. 1999 Mar-Apr;10(2):271-8. doi: 10.1021/bc980099n.
Multiple sialic acid (SA) residues conjugated to a linear polyacrylamide backbone are more effective than monomeric SA at inhibiting influenza-induced agglutination of red blood cells. However, "polymeric inhibitors" based on polyacrylamide backbones are cytotoxic. Dendritic polymers offer a nontoxic alternative to polyacrylamide and may provide a variety of potential synthetic inhibitors of influenza virus adhesion due to the wide range of available polymer structures. We evaluated several dendritic polymeric inhibitors, including spheroidal, linear, linear-dendron copolymers, comb-branched, and dendrigraft polymers, for the ability to inhibit virus hemagglutination (HA) and to block infection of mammalian cells in vitro. Four viruses were tested: influenza A H2N2 (selectively propagated two ways), X-31 influenza A H3N2, and sendai. The most potent of the linear and spheroidal inhibitors were 32-256-fold more effective than monomeric SA at inhibiting HA by the H2N2 influenza virus. Linear-dendron copolymers were 1025-8200-fold more effective against H2N2 influenza, X-31 influenza, and sendai viruses. The most effective were the comb-branched and dendrigraft inhibitors, which showed up to 50000-fold increased activity against these viruses. We were able to demonstrate significant (p < 0.001) dose-dependent reduction of influenza infection in mammalian cells by polymeric inhibitors, the first such demonstration for multivalent SA inhibitors. Effective dendrimer polymers were not cytotoxic to mammalian cells at therapeutic levels. Of additional interest, variation in the inhibitory effect was observed with different viruses, suggesting possible differences due to specific growth conditions of virus. SA-conjugated dendritic polymers may provide a new therapeutic modality for viruses that employ SA as their target receptor.
与线性聚丙烯酰胺主链共轭的多个唾液酸（SA）残基在抑制流感诱导的红细胞凝集方面比单体SA更有效。然而，基于聚丙烯酰胺主链的“聚合物抑制剂”具有细胞毒性。树枝状聚合物为聚丙烯酰胺提供了一种无毒的替代物，并且由于可用聚合物结构的广泛多样性，可能提供多种潜在的流感病毒粘附合成抑制剂。我们评估了几种树枝状聚合物抑制剂，包括球状、线性、线性-树枝状共聚物、梳状支链和树枝状接枝聚合物，以研究它们在体外抑制病毒血凝（HA）和阻断哺乳动物细胞感染的能力。测试了四种病毒：甲型H2N2流感病毒（通过两种方式选择性繁殖）、X-31甲型H3N2流感病毒和仙台病毒。在抑制H2N2流感病毒的HA方面，最有效的线性和球状抑制剂比单体SA有效32至256倍。线性-树枝状共聚物对H2N2流感病毒、X-31流感病毒和仙台病毒的效力要高1025至8200倍。最有效的是梳状支链和树枝状接枝抑制剂，它们对这些病毒的活性提高了50000倍。我们能够证明聚合物抑制剂可使哺乳动物细胞中的流感感染显著（p < 0.001）剂量依赖性降低，这是多价SA抑制剂的首次此类证明。有效的树枝状聚合物在治疗水平上对哺乳动物细胞无细胞毒性。另外值得注意的是，观察到不同病毒的抑制效果存在差异，这表明可能由于病毒的特定生长条件而存在差异。SA共轭树枝状聚合物可能为以SA作为靶受体的病毒提供一种新的治疗方式。
