Hildert Bronkhorst¹, Marcel Schaaf²


(1) Leiden University, Institute of Biology,, Leiden, Netherlands. (2) Leiden University, Institute of Biology,, Leiden, Netherlands. 

Hildert Bronkhorst¹, Meg I. Ferguson¹, Sanne Kroos², Arieke S.B. Kampstra², Adriana A. Anguelova¹, Joesephina A. Saager¹, René E.M. Toes², Nathaniel I. Martin¹, Annemarie H. Meijer¹, Erin Faught¹, Marcel J.M. Schaaf¹

¹Institute of Biology Leiden, Leiden University, Leiden, The Netherlands

²Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

Glucocorticoids are widely used anti-inflammatory drugs of which the clinical use is limited by the severity of their side effects. In the past decades, the field has focused on the modification of glucocorticoids to limit their side effects while retaining the anti-inflammatory efficacy. Inspired by a class of selective anti-inflammatory natural compounds, the ginsenosides, we conjugated the disaccharide gentiobiose to the 21-position of prednisolone. Interestingly, this gentiobiose-prednisolone conjugate shows anti-inflammatory action but has significantly reduced side effects. In zebrafish, gentiobisose-prednisolone inhibits neutrophil migration after tail fin amputation, but does not affect tail fin regeneration. In a mouse model for arthritis, gentiobiose-prednisolone lowers the arthritis score, but has no impact on insulin levels and thymus weight. Currently, we are investigating the mechanism behind this selective action in two ways. First, we study the metabolism of gentiobiose-prednisolone, particularly if it is hydrolyzed in inflamed tissue. Second, we examine if and how gentiobiose-prednisolone and its metabolites interact with the glucocorticoid receptor, principally if they act as a dissociated agonists.