Development of hybrid molecules targeting glucocorticoid and peroxisome proliferator-activated receptor-based heterodimers to combat inflammation

01 November 2023 → 31 October 2027
Regional and community funding: Special Research Fund
Research disciplines
  • Natural sciences
    • Characterisation of biologically active (macro)molecules
  • Medical and health sciences
    • Endocrinology
Bivalent ligands Nuclear receptor heterodimers Inflammation
Project description

According to the World Health Organization, chronic inflammatory diseases should be regarded as one of the greatest threats to human health. Glucocorticoids have widespread use in the clinic and constitute the primary treatment option for e.g. asthma, allergy, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. Unfortunately, prolonged glucocorticoid treatment at higher doses is severely hampered by side effects and a gradual emergence of resistance. Despite these problems, the glucocorticoid receptor will remain a crucial drug target in inflammation because of its efficacy, combined with the low cost of its agonists. We have solid evidence in place that the nuclear receptors GR and PPARα can interact and that targeting heterodimers between GR and PPARα with bivalent ligands leads to an enhanced therapeutic benefit due to their sustained anti-inflammatory properties combined with considerably better side effect marker profiles. This project aims to synthesize metabolically stable bivalent ligands connecting a GR agonist (e.g. dexamethasone) via a linker to a PPARα agonist (e.g. pemafibrate) through feasible and efficient procedures. Additionally, these novel conjugates will be characterized in terms of anti-inflammatory activity, ability to promote GR-PPARα heterodimer formation, side effect marker profiles, and eADME-Tox properties, which altogether will establish their value as a novel therapeutic agents to proceed to chronic inflammation models.