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Sci Rep. 2017 Nov 10;7(1):15307. doi: 10.1038/s41598-017-15338-0.

Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP.

Author information

1
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.
2
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
3
Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
4
Aimm Therapeutics, Amsterdam, The Netherlands.
5
Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.
6
German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
7
Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. k.f.vandegraaf@amc.uva.nl.
8
Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. k.f.vandegraaf@amc.uva.nl.

Abstract

The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC50 5.1 µM), zafirlukast (IC50 6.5 µM), TRIAC (IC50 6.9 µM), and sulfasalazine (IC50 9.6 µM). Chicago sky blue 6B (IC50 7.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.

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