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

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.

• Authors: Joanne M Donkers, Benno Zehnder, Gerard J P van Westen, Mark J Kwakkenbos, Adriaan P IJzerman, Ronald P J Oude Elferink, Ulrich Beuers, Stephan Urban, Stan F J van de Graaf
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 15307 (11 10 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 29127322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Indoles
• Lipopeptides
• Organic Anion Transporters, Sodium-Dependent
• Phenylcarbamates
• Sulfonamides
• Symporters
• Tosyl Compounds
• myrcludex-B
• Rosiglitazone
• Triiodothyronine
• sodium-bile acid cotransporter
• pontamine sky blue
• 3,3',5-triiodothyroacetic acid
• Sulfasalazine
• Trypan Blue
• zafirlukast

Topics

• Animals
• Antiviral Agents (pharmacology)
• Dogs
• Hepatitis B (drug therapy, metabolism, pathology)
• Hepatitis B virus (metabolism)
• Hepatitis D (drug therapy, metabolism, pathology)
• Hepatitis Delta Virus (metabolism)
• Humans
• Indoles
• Lipopeptides (pharmacology)
• Madin Darby Canine Kidney Cells
• Organic Anion Transporters, Sodium-Dependent (antagonists & inhibitors, genetics, metabolism)
• Phenylcarbamates
• Rosiglitazone (pharmacology)
• Sulfasalazine (pharmacology)
• Sulfonamides
• Symporters (antagonists & inhibitors, genetics, metabolism)
• Tosyl Compounds (pharmacology)
• Triiodothyronine (analogs & derivatives, pharmacology)
• Trypan Blue (pharmacology)
• Virus Internalization (drug effects)