Abstract
Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) entry. However, little is known regarding whether NTCP is involved in regulating the postentry steps of the HBV life cycle. Here, we found that NTCP expression upregulated HBV transcription at the postentry step and that the NTCP-targeting entry inhibitor Myrcludex B (MyrB) effectively suppressed HBV transcription both in an HBV in vitro infection system and in mice hydrodynamically injected with an HBV expression plasmid. Mechanistically, NTCP upregulated HBV transcription via farnesoid X receptor α (FxRα)-mediated activation of the HBV EN2/core promoter at the postentry step in a manner that was dependent on the bile acid (BA)-transport function of NTCP, which was blocked by MyrB. Our findings uncover a novel role for NTCP in the HBV life cycle and provide a reference for the use of novel NTCP-targeting entry inhibitors to suppress HBV infection and replication.
Highlights
With ~240 million chronically infected individuals worldwide, Hepatitis B virus (HBV) infection remains a major global health burden[1]
The levels of HBsAg and HBeAg in the culture supernatants were increased by approximately 3.3fold and 2.2-fold, respectively, in the presence of the needed.As sodium taurocholate cotransporting polypeptide (NTCP) (Fig. 1c). These results suggest that NTCP expression may facilitate HBV replication at the postentry step
NTCP has been shown to act as a functional receptor and major host-specific restriction factor for HBV infection[4,26]
Summary
With ~240 million chronically infected individuals worldwide, Hepatitis B virus (HBV) infection remains a major global health burden[1]. As sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the functional receptor for HBV entry[4], entry inhibitors targeting NTCP offer a promising novel therapeutic option[5]. One such entry inhibitor is Myrcludex B (MyrB), a myristoylated synthetic lipopeptide comprising 47 amino acids derived from the preS1 domain of the HBV large surface protein. MyrB can efficiently block de novo HBV and HDV infection both in vitro[6] and in vivo[7]. MyrB was recently confirmed to be well tolerated in healthy volunteers[9], with antiviral efficacy against HBV and HDV infection[10]
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