Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

Show full item record



Permalink

http://hdl.handle.net/10138/325604

Citation

Kirstgen , M , Lowjaga , K A A T , Müller , S F , Goldmann , N , Lehmann , F , Alakurtti , S , Yli-Kauhaluoma , J , Klebe , D & Geyer , J 2020 , ' Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids ' , Scientific Reports , vol. 10 , no. 1 , 21772 . https://doi.org/10.1038/s41598-020-78618-2

Title: Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids
Author: Kirstgen, Michael; Lowjaga, Kira Alessandra Alicia Theresa; Müller, Simon Franz; Goldmann, Nora; Lehmann, Felix; Alakurtti, Sami; Yli-Kauhaluoma, Jari; Klebe, Dieter; Geyer, Joachim
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2020-12-10
Language: eng
Number of pages: 16
Belongs to series: Scientific Reports
ISSN: 2045-2322
URI: http://hdl.handle.net/10138/325604
Abstract: 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.
Subject: 11832 Microbiology and virology
317 Pharmacy
COTRANSPORTING POLYPEPTIDE NTCP
BILE-ACID TRANSPORTER
MEMBRANE TRANSPORTER
CYCLOSPORINE-A
CELL-LINES
IN-VITRO
DERIVATIVES
INFECTION
IDENTIFICATION
HEPATOCYTES
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
s41598_020_78618_2.pdf 5.007Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record