Synthesis of novel, multivalent glycodendrimers as ligands for HIV-1 gp120
Synthesis of novel, multivalent glycodendrimers as ligands for HIV-1 gp120
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DOI：
10.1021/bc034156a
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发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Schengrund, CL
中科院分区：
文献类型：
--
作者：
Kensinger, RD;Yowler, BC;Schengrund, CL
多价新糖缀合物是研究碳水化合物-蛋白质相互作用的有价值的工具。为了研究HIV-1 gp 120与其报告的替代糖脂受体半乳糖基神经酰胺（GalCer）和硫苷脂的相互作用，合成了半乳糖和硫酸化半乳糖衍生的树枝状聚合物，通过表面等离子体共振分析其作为rgp 120的配体，并测试其抑制HIV-1感染CXCR 4和CCR 5表达指示细胞的能力。通过胺偶联间隔臂衍生的半乳糖残基（硫酸化或非硫酸化的）到聚（丙烯亚胺）树枝状聚合物（第1-5代）来制备四个不同系列的糖树枝状聚合物。一系列糖树枝状聚合物是从纯化的天然GalCer的神经酰胺糖衍生物制备的，另一系列是从化学合成的3-（β-D-吡喃半乳糖基硫代）丙酸制备的。使用新化合物3-（β-D-3-磺基半乳糖基硫代）丙酸完成了3-磺基半乳糖基衍生的树枝状聚合物的合成。第四系列通过3-（β-D-吡喃半乳糖基硫代）丙酸官能化树枝状聚合物的无规硫酸化制备。的碳水化合物部分的结构进行了确认，通过NMR和不同的glycodendrimers的平均分子量和多分散性进行了测定，使用MALDI-TOF MS。表面等离子体共振研究发现，rgp 120 IIIB绑定到测试与纳摩尔亲和力的衍生树枝状聚合物，和葡聚糖硫酸盐与皮摩尔亲和力。这些化合物抑制U373-MAGI-CCR 5细胞被HIV-1 Ba-L感染的有效性的体外研究表明，硫酸化的糖树枝状聚合物是比非硫酸化的糖树枝状聚合物更好的抑制剂，但不如硫酸葡聚糖有效。
Multivalent neoglycoconjugates are valuable tools for studying carbohydrate-protein interactions. To study the interaction of HIV-1 gp120 with its reported alternate glycolipid receptors, galactosyl ceramide (GalCer) and sulfatide, galactose- and sulfated galactose-derivatized dendrimers were synthesized, analyzed as ligands for rgp120 by surface plasmon resonance, and tested for their ability to inhibit HIV-1 infection of CXCR4- and CCR5-expressing indicator cells. Four different series of glycodendrimers were made by amine coupling spacer-arm derivatized galactose residues, either sulfated or nonsulfated, to poly(propylenimine) dendrimers, generations 1-5. One series of glycodendrimers was prepared from the ceramide saccharide derivative of purified natural GalCer, and another was from chemically synthesized 3-(beta-D-galactopyranosylthio)propionic acid. Synthesis of 3-sulfogalactopyranosyl-derivatized dendrimers was accomplished using the novel compound, 3-(beta-D-3sulfogalactopyranosylthio)propionic acid. The fourth series was made by random sulfation of the 3-(beta-D-galactopyranosylthio)propionic acid functionalized dendrimers. Structures of the carbohydrate moieties were confirmed by NMR, and the average molecular weights and polydispersities of the different glycodendrimers were determined using MALDI-TOF MS. Surface plasmon resonance studies found that rgp120 IIIB bound to the derivatized dendrimers tested with nanomolar affinity, and to dextran sulfate with picomolar affinity. In vitro studies of the effectiveness of these compounds at inhibiting infection of U373-MAGI-CCR5 cells by HIV-1 Ba-L indicated that the sulfated glycodendrimers were better inhibitors than the nonsulfated glycodendrimers, but not as effective as dextran sulfate.