Semi-synthetic studies on astragaloside VII and immunomodulatory activities of the derivatives

Adjuvants have been used in vaccine sector since 1920s to increase the immunogenicity of antigens, reduce the dosage and minimize frequency of immunizations [1]. The use of saponins as adjuvant in the prophylactic/therapeutic human and veterinary vaccines, and investigation of their immunomodulatory activities have gained importance in recent years [2],[3]. Astragaloside VII (AST VII), a triterpenoid saponin isolated from Astragalus species, stimulates Th1 mediated immune response, antigen-specific antibody response and splenocyte proliferation [4],[5].

The main goals of this study were the synthesis of immunologically active analogs of AST VII and investigating immunomodulatory properties of these compounds in human whole blood. The analogs of AST VII were prepared by selective oxidation of the primary alcohols to carboxylic acids in glucose residues to afford DC-AST VII, and followed by amidation reaction to give DAC-AST VII. AST VII and its analogs were evaluated for their immunomodulatory properties based on their effects on cytokine level alterations (IL-2, IFN-γ, IL-17A, IL-1β, IL-4, TNF-α) using ELISA method.

As a result, between 2 to 32 μg/mL concentrations, the compounds significantly reduced Th1 mediated cytokines such as IL-2, IFN-γ, and TNF-α ranging from 1.10 to 8.46-fold compared to the control (PMA-ionomycin), while inducing IL-1β and IL-17A. The most potent compounds were: DAC-AST VII (3.32-fold) for production of IL-1β, and AST VII (5.05-fold) for production of IL-17A. According to the cytokine release profiles, these compounds as single entities or in combination might have chance to be developed as vaccine adjuvants, and further studies are in progress to elucidate the mechanism of action.

Fig. 1 Chemical structure of AST VII analogs

• References

• 1 Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med 2013; 19: 1597-1608
• 2 Garçon N, Di Pasquale A. From discovery to licensure, the Adjuvant System story. Hum Vaccin Immunother 2017; 13: 19-33
• 3 Morelli AB, Maraskovsky E. . ISCOMATRIX Adjuvant in the development of prophylactic and therapeutic vaccines. Immunopotentiators in Modern Vaccines: Second Edition. 2016 87. 311-332
• 4 Nalbantsoy A, Nesil T, Erden S, Calış I, Bedir E. Adjuvant effects of Astragalus saponins macrophyllosaponin B and astragaloside VII. J Ethnopharmacol 2011; 134: 897-903
• 5 Nalbantsoy A, Nesil T, Yilmaz-Dilsiz Ö, Aksu G, Khan S, Bedir E. Evaluation of the immunomodulatory properties in mice and in vitro anti-inflammatory activity of cycloartane type saponins from Astragalus species. J Ethnopharmacol 2012; 139: 574-581