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具有免疫刺激活性的半合成三萜皂苷衍生物的开发。

Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity.

作者信息

Marciani D J, Press J B, Reynolds R C, Pathak A K, Pathak V, Gundy L E, Farmer J T, Koratich M S, May R D

机构信息

Galenica Pharmaceuticals, Inc., Frederick, MD 21701, USA.

出版信息

Vaccine. 2000 Jul 15;18(27):3141-51. doi: 10.1016/s0264-410x(00)00118-3.

Abstract

Aldehyde-containing triterpene saponins have adjuvant properties, but only those from Quillaja saponaria Molina stimulate the production of cytotoxic T lymphocytes (CTL) against exogenous antigens. Quillaja saponins have two normonoterpene ester moieties, linked linearly to their fucosyl residue, that play a critical role in the stimulation of CTL. These ester moieties are also responsible for these saponins' instability and toxicity. Based on the structure-activity relationships for the different groups of Q. saponaria saponins, new semi-synthetic analogs were developed that have the adjuvanticity of quillaja saponins, yet with less toxicity and greater stability in aqueous solutions. The quillaja saponin analogs were prepared by replacing their hydrolytically unstable ester groups with another lipophilic chain linked by a stable amide bond on these saponins' glucuronic acid residue. One of these analogs, GPI-0100, is a dodecylamide saponin derivative that stimulates an antibody isotype profile that corresponds to a Th1 type immune response, as well as CTL production against exogenous antigens.

摘要

含醛三萜皂苷具有佐剂特性,但只有来自皂树(Quillaja saponaria Molina)的皂苷能刺激针对外源性抗原的细胞毒性T淋巴细胞(CTL)产生。皂树皂苷有两个与岩藻糖残基线性相连的降单萜酯部分,它们在CTL的刺激中起关键作用。这些酯部分也导致了这些皂苷的不稳定性和毒性。基于皂树不同组皂苷的构效关系,开发了新的半合成类似物,它们具有皂树皂苷的佐剂活性,但毒性较小且在水溶液中稳定性更高。皂树皂苷类似物是通过用另一个通过稳定酰胺键连接的亲脂性链取代其在这些皂苷葡萄糖醛酸残基上水解不稳定的酯基而制备的。其中一种类似物GPI-0100是一种十二烷基酰胺皂苷衍生物,它能刺激与Th1型免疫反应相对应的抗体亚型谱,以及针对外源性抗原的CTL产生。

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