Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle

Abstract

Worldwide there are approximately 240million individuals chronically infected with the hepatitis B virus (HBV), including 15-20million coinfected with the hepatitis delta virus (HDV). Treatments available today are not fully efficient and often associated to important side effects and development of drug resistance. Targeting the HBV/HDV entry step using preS1-specific lipopeptides appears as a promising strategy to block viral entry for both HBV and HDV (Gripon et al., 2005; Petersen et al., 2008). Recently, the human Sodium Taurocholate Cotransporting Polypeptide (hNTCP) has been identified as a functional, preS1-specific receptor for HBV and HDV. This groundbreaking discovery has opened a very promising avenue for the treatment of chronic HBV and HDV infections. Here we investigated the ability of FDA approved therapeutics with documented inhibitory effect on hNTCP cellular function to impair viral entry using a HDV in vitro infection model based on a hNTCP-expressing Huh7 cell line. We demonstrate the potential of three FDA approved molecules, irbesartan, ezetimibe, and ritonavir, to alter HDV infection in vitro.

Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor

“…These seminal findings established NTCP as an HBV and HDV receptor, a demonstration that has been independently confirmed and extended (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Consequently, NTCP substrates or inhibitors such as tauroursodeoxycholic acid (TUDCA), cyclosporine, irbesartan, and ritonavir could suppress ccHBV or HDV infection (18,(20)(21)(22)(23)(24). Nevertheless, NTCP-reconstituted HepG2 cells cultured in the presence of DMSO reportedly released up to 100 times more HBeAg than differentiated HepaRG cells after ccHBV infection, but comparable amounts of HBsAg (18).…”

A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

“…As the immunosuppressive activity of cyclosporine was dispensable for anti-HBV activity, we showed that nonimmunosuppressive derivatives, including alisporivir, which is under clinical development for treatment of chronic hepatitis C, significantly inhibited HBV infection, suggesting that these compounds are potential anti-HBV candidates (17). In addition, three FDA-approved agents, irbesartan, ezetimibe, and ritonavir, which are already known to inhibit NTCP transporter activity, reduced LHBs-dependent viral infection (32)(33)(34)36). Although already known NTCP inhibitors have been reported to inhibit viral infection, there is no report identifying novel compounds that target NTCP and inhibit HBV infection.…”

“…In addition, vanitaracin A was also effective against HDV infection, as in the case of anti-HBV entry inhibitors reported so far (32,35,51). Coinfection of HDV with HBV occurs in ϳ15 million people worldwide, and HDV infection causes more severe viral hepatitis than does hepatitis B (52)(53)(54).…”

Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na+-dependent taurocholate cotransporting polypeptide activity

“…However, further experiments and clinical survey are needed to determine whether irbesartan will be effective against HBV infection and spread in vivo. Considering that HBV and its satellite virus hepatitis D virus (HDV) both utilize NTCP for their entry, we hypothesize that irbesartan could also exert anti-HDV effects which was reported very recently (Blanchet et al, 2014) and this might be helpful for HBV/HDV coinfection therapy.…”