C5: Hit-to-lead development of selective HBV/HDV entry inhibitors
Prof. Dr. Dieter Glebe
Institut für Medizinische Virologie
Phone: +49 (0)641-99 41246
Prof. Dr. Joachim Geyer
Institut für Pharmakologie und Toxikologie
Phone: +49 (0)641-99 38404
Infections with the Hepatitis B (HBV) and D (HDV) viruses are the main cause of hepatocellular carcinoma and liver cirrhosis as a consequence of chronic hepatitis. Although an effective prophylactic vaccine is available, therapeutic options are highly limited, in particular for HDV. A promising novel drug target to block HBV/HDV virus entry into hepatocytes is represented by the hepatic bile acid carrier NTCP (Na+/taurocholate co-transporting polypeptide) that has been identified as the bona fide hepatic receptor for HBV/HDV. So far, more than 200 compounds from different compound classes have been tested and corresponding 3D structure-activity-relationship (QSAR) models have been generated. Furthermore, a pharmacophore model for HBV/HDV entry inhibitors was established. Virtual compound libraries have already been screened with these models and further effective hits have been identified.
Development of oral and selective HBV/HDV entry inhibitors that specifically block virus binding to NTCP, without tackling its physiological bile acid transport function. Hit compounds will be further developed into lead structures by means of molecular drug design.
DRUID Collaboration partners:
B1 Diederich/Kolb, B3 Rahlfs/Kolb/van Zandbergen, D2 Pfeiffer/Zeuzem/Hildt, E3 Rahlfs/Przyborski, E6 Schiffmann/Laux
References C5:1. *Kirstgen et al. (2020) Sci Rep 10:21772 2. *Grosser et al. (2021) Front Mol Biosci 8:689757 3. *Kirstgen et al. (2021) Viruses 13:666 4. *Kirstgen et al. (2021) Viruses 13:1489.