Anti-inflammatory glycosides from plants: Identification of cellular targets and examination of structure–function relationships

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The unique diversity of plant glycosides harbors a considerable potential to derive a natural drug. In the past, we focused on the identification of glycosylated triterpenoids as endosomal escape enhancers in targeted tumor therapies. We identified a particular saponin, SO1861, from Saponaria officinalis L. and demonstrated in cell culture that tumor-targeted toxins can become enhanced in their cell killing efficacy up to 2,500,000-fold, which resulted in a broadening of the therapeutic window in mice between 10-fold to 500-fold. The tumor regression across all mouse studies was about 90% and the required dose was only 2% of the dose used for a treatment without SO1861. The lower dose resulted in decreased side effects and reduced immunogenicity. We demonstrated that the augmentative effect relies on an enhanced transfer of the toxin moiety across the membrane of the endocytic vesicle into the cytosol. It is important to emphasize that this specific outcome of SO1861 occurs at concentrations that are far below the concentration required to trigger general saponin effects (such as hemolysis) and is based on the particular and unique chemical structure of the aglycone and sugar chains.Investigations of anti-inflammatory saponins are of increasing interest. More than 25% of scientific papers on this topic are published within the last 4 years. There is no doubt that certain saponins have an anti-inflammatory potential, however, most investigations applied semi-purified saponin mixtures or total saponins, the results are descriptive and detailed knowledge on structure–function relationships is missing. It has not been shown to date, which molecules inside the cell are the targets of the saponins. It is hypothesized that the various anti-inflammatory effects of saponins are based on specific interactions that can be attributed to only a defined subgroup of saponins with particular chemical functionalities. We will first select commercially available saponins with known structure and described anti-inflammatory effects to identify primary cellular targets and to reveal structure–function relationships. In particular, we want to demonstrate how interactions between saponins and targets result in changes in the cytokine equipment. After confirming the anti-inflammatory effects of single saponins in cell culture, we will continue with labeling studies, binding assays, localization studies, inhibitor experiments, membrane assays and tracking of biological pathways. Identification and structural elucidation of new saponins with similar behavior will then be used to refine and generalize the observed molecular mechanisms. We will determine important structural characteristics (aglycone, composition of sugar residues, sugar linkage, stereoisomer configurations) by MALDI and NMR techniques. If successful, it is planned in a following period to investigate the molecular mechanism of the anti-inflammatory effects in vivo.