ergosterol-5-8-peroxide and Hepatitis-B

Hepatitis B virus (HBV) infection is a worldwide health problem, and chronic infection can cause many diseases ranging from liver fibrosis to hepatocellular carcinoma (HCC) by complicated mechanisms. Currently, the treatment of HBV infection mainly depends on interferons (IFNs) and nucleotide analogues (NAs); however, both have some limitations. In 2012, sodium taurocholate cotransporting polypeptide (NTCP) was identified as the entry receptor of HBV. Based upon this groundbreaking discovery, a series of molecules have been gradually developed and evaluated to discover novel entry inhibitors targeting NTCP. However, only two macromolecules have been used for potential clinical applications so far. In this Perspective, we focus on summarizing the structural features that convey the biological functions of NTCP, as well as further discuss the anti-HBV activity and selectivity of inhibitors in HBV-related diseases, which should provide clues in the future for the discovery of drug candidates targeting NTCP.

Topics: Carcinoma, Hepatocellular; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Hepatocytes; Humans; Interferons; Liver Neoplasms; Nucleotides; Organic Anion Transporters, Sodium-Dependent; Symporters; Virus Internalization

Hepatitis B virus (HBV) infection leads to severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). More than 257 million individuals are chronically infected, particularly in the Western Pacific region and Africa. Although nucleotide and nucleoside analogues (NUCs) and interferons (IFNs) are the standard therapeutics for HBV infection, none eradicates HBV covalently closed circular DNA (cccDNA) from the infected hepatocytes. In addition, long-term treatment with NUCs increases the risk of developing drug resistance and IFNs may cause severe side effects in patients. Thus, a novel HBV therapy that can achieve a functional cure, or even complete elimination of the virus, is highly desirable. Regarding the HBV life cycle, agents targeting the entry step of HBV infection reduce the intrahepatic cccDNA pool preemptively. The initial entry step in HBV infection involves interaction between the pre-S1 domain of the large hepatitis B surface protein (LHBsAg) and the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. In this study, ergosterol peroxide (EP) was identified as a new inhibitor of HBV entry. EP inhibits an early step of HBV entry into DMSO-differentiated immortalized primary human hepatocytes HuS-E/2 cells, which were overexpressed NTCP. Also, EP interfered directly with the NTCP-LHBsAg interaction by acting on the NTCP. In addition, EP had no effect on HBV genome replication, virion integrity or virion secretion. Finally, the activity of EP against infection with HBV genotypes A-D highlights the therapeutic potential of EP for fighting HBV infection.

Topics: DNA, Circular; Ergosterol; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Organic Anion Transporters, Sodium-Dependent; Symporters; Virus Internalization; Virus Replication