C5: Hit-to-lead development of selective HBV/HDV entry inhibitors

Principal Investigator:

Prof. Dr. Dieter Glebe

Institut für Medizinische Virologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen
Phone: +49 (0)641-99 41246
E-Mail: dieter.glebe(at)viro.med.uni-giessen(dot)de


Principal Investigator:

Prof. Dr. Joachim Geyer

Institut für Pharmakologie und Toxikologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen
Phone: +49 (0)641-99 38404
E-Mail: joachim.m.geyer(at)vetmed.uni-giessen(dot)de


Project description:

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.

NTCP is a physiological bile acid transporter in the plasma membrane of liver cells. NTCP is also the hepatic receptor for HBV and HDV. HBV/HDV entry inhibitors should selectively block NTCP viral receptor function. 3D QSAR and pharmacophore models help identify novel NTCP inhibitors.

 

Scientific goal:

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.