Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activity

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, th at play a critical role in the stimulation of CTL. These ester moieties are also responsible for these saponins' instability and toxicity. Based on th e structure-activity relationships for the different groups of Q. saponaria saponins, new semi-synthetic analogs were developed that have the adjuvant icity 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 l inked by a stable amide bond on these saponins' glucuronic acid residue. On e of these analogs, GPI-0100, is a dodecylamide saponin derivative that sti mulates an antibody isotype profile that corresponds to a Th1 type immune r esponse, as well as CTL production against exogenous antigens. (C) 2000 Els evier Science Ltd. All rights reserved.