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.Donkers JM1, Zehnder B2, van Westen GJP3, Kwakkenbos MJ4, IJzerman AP3, Oude Elferink RPJ1,5, Beuers U1,5, Urban S2,6, van de Graaf SFJ7,8. Author information 1Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.2Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.3Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.4Aimm Therapeutics, Amsterdam, The Netherlands.5Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands.6German Center for Infection Research, Heidelberg University, Heidelberg, Germany.7Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. [email protected].8Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands. [email protected].
AbstractThe 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.