TY - JOUR
T1 - Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
AU - Kirstgen, Michael
AU - Lowjaga, Kira Alessandra Alicia Theresa
AU - Müller, Simon Franz
AU - Goldmann, Nora
AU - Lehmann, Felix
AU - Alakurtti, Sami
AU - Yli-Kauhaluoma, Jari
AU - Glebe, Dieter
AU - Geyer, Joachim
N1 - Funding Information:
The authors want to acknowledge Edda Wacker for critical reading of the manuscript and Anita Neubauer for her competent support in carrying out the experiments. We also thank Dr. Gary Grosser for his excellent scientific support regarding the setup of inhibition studies. This study was supported by Flex Funds from the LOEWE-Center DRUID (Novel Drug Targets against Poverty-related and Neglected Tropical Infectious Diseases) and in part by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 197785619 – SFB 1021 and the Foundation for Research of Natural Resources in Finland, Marjatta ja Eino Kollin Säätiö, and the COST Action CM-0801 (New drugs for neglected diseases).
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/10
Y1 - 2020/12/10
N2 - Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP's physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure-activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.
AB - Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as the high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP's physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure-activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.
UR - http://www.scopus.com/inward/record.url?scp=85097497817&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-78618-2
DO - 10.1038/s41598-020-78618-2
M3 - Article
C2 - 33303817
SN - 2045-2322
VL - 10
SP - 21772
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 21772
ER -