Abstract
Identification of Na+/taurocholate co-transporting polypeptide (NTCP) as high-affinity hepatic entry receptor for the Hepatitis B and D viruses (HBV/HDV) opened the field for target-based development of cell-entry inhibitors. However, most of the HBV/HDV entry inhibitors identified so far also interfere with the physiological bile acid transporter function of NTCP. The present study aimed to identify more virus-selective inhibitors of NTCP by screening of 87 propanolamine derivatives from the former development of intestinal bile acid reabsorption inhibitors (BARIs), which interact with the NTCP-homologous intestinal apical sodium-dependent bile acid transporter (ASBT). In NTCP-HEK293 cells, the ability of these compounds to block the HBV/HDV-derived preS1-peptide binding to NTCP (virus receptor function) as well as the taurocholic acid transport via NTCP (bile acid transporter function) were analyzed in parallel. Hits were subsequently validated by performing in vitro HDV infection experiments in NTCP-HepG2 cells. The most potent compounds S985852, A000295231, and S973509 showed in vitro anti-HDV activities with IC50 values of 15, 40, and 70 µM, respectively, while the taurocholic acid uptake inhibition occurred at much higher IC50 values of 24, 780, and 490 µM, respectively. In conclusion, repurposing of compounds from the BARI class as novel HBV/HDV entry inhibitors seems possible and even enables certain virus selectivity based on structure-activity relationships.
Highlights
Hepatitis B (HBV) and D (HDV) virus infections are the main cause of hepatocellular carcinoma (HCC) and liver cirrhosis as consequences of chronic hepatitis
For inhibition of myr-preS12-48 lipopeptide binding to Na+/taurocholate co-transporting polypeptide (NTCP), 87 propanolamine derivatives were used as potential inhibitors
Many recent studies focused on NTCP inhibition in order to prevent virus entry into hepatocytes, using cyclosporine A and other cyclosporine derivatives [23,24,25,26], ezetimibe [10], irbesartan [27], ritonavir [28], ()-epigallocatechin-3-gallate [29], vanitaracin A [30], Ro41-5253 [31], proanthocyanidin [32], zafirlukast [33], sulfasalazine [33], and Chicago Sky Blue 6B [33]
Summary
Hepatitis B (HBV) and D (HDV) virus infections are the main cause of hepatocellular carcinoma (HCC) and liver cirrhosis as consequences of chronic hepatitis. HBV and HDV virus binding to hepatocytes shares the identical mechanism [5]. 5% of all chronic HBV carriers are superinfected with HDV [1]. This results in more rapid disease progression, increased mortality rates, and increased incidence of HCC and liver cirrhosis [6]. Nucleoside reverse transcriptase inhibitors and interferon are used as a common therapy to keep HBV/HDV associated chronic hepatitis under control. Interferon therapy is highly prone to adverse drug reactions and nucleoside reverse transcriptase inhibitors have to be given life-long [7,8]
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