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

Abstract

Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules thatC hronic hepatitis B virus (HBV) infection, constituting a public health problem, with an estimated 240 million carriers worldwide (1), elevates the risk of development of liver cirrhosis and hepatocellular carcinoma (2). Antiviral agents against HBV include nucleos(t)ide analogs (NAs) and interferons (IFNs), which can achieve significant reductions in HBV loads (3). Although IFN-␣ and its pegylated form (peg-IFN-␣) modulate host immune responses to HBV infection or directly inhibit HBV replication in hepatocytes, these regimens show low tolerability because of serious adverse effects (3, 4). NAs, including lamivudine (LMV), adefovir, entecavir (ETV), tenofovir, and telbivudine, inhibit reverse transcription to suppress HBV replication, but longterm treatment with some of these NAs often results in selection for a significant number of drug-resistant viruses, which decreases treatment efficacy; i.e., the introduction of two substitutions, L180M and M204V, in the polymerase region leads to resistance to LMV, and an additional mutation of either T184, S202, or M250 with the L180M/M204V mutations confers further ETV resistance (5). More notably, it is difficult for the above-mentioned anti-HBV drugs to completely eliminate HBV from infected cells. Future antiviral strategies include multidrug treatment with an existing drug and a new anti-HBV agent. Consequently, there is a

A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins

“…Among these proteins, the LHBs, especially the amino terminal 2‐48 amino acids (aa) of the preS1 region, plays an essential role in the entry process through binding to an entry receptor, sodium taurocholate cotransporting polypeptide (NTCP) . To date, selective HBV entry inhibitors have been identified, including myrcludex‐B, bile acids, cyclosporins, ezetimibe, ritonavir, irbesartan, and vanitaracin A, all of which have been shown to directly target NTCP . It was also found that all of these agents can impair the original function of NTCP, that is, sodium‐dependent bile acid uptake into hepatocytes, through molecular interaction with NTCP .…”

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

“…Interestingly, the amino acid motifs of NTCP critical for HBV entry overlap with that for bile salts uptake by NTCP, and the inhibition of HBV entry by NTCP natural ligands has been observed in cell cultures (Yan et al, 2014). Furthermore, a tricyclic polyketide, vanitaracin A, has been shown to inhibit HBV and HDV entry by directly interacting with NTCP and inhibiting its transporter activity (Kaneko et al, 2015). Nonetheless, it is worth noting that certain CsA analogs that abrogate the immunosuppressive activity possess a stronger anti-HBV activity without interfering NTCP transporter function, perhaps through an allosteric mechanism (Shimura et al, 2017).…”

Drugs in Development for Hepatitis B

“…Entry inhibitors are of particular interest since inhibiting viral entry could block virus replication before cccDNA, the persistent viral reservoir, is formed [109]. Sodium taurocholate co-transporting polypeptide (NTCP), a key bile acid transporter whose primary role is transport of bile salts from the portal blood into the liver, is mainly expressed in hepatocytes at the basolateral membrane [110].…”