Novel NTCP ligand dimeric bile acid conjugated with ASO reduce hepatitis B virus surface antigen in vivo

Abstract

Hepatitis B virus (HBV) specifically infects hepatocytes and causes severe liver diseases. However, functional cure is rarely attainable by current treatment modalities. Anti-sense oligonucleotide (ASO), which targets pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication, has been studied as a novel treatment strategy for HBV cure and can be conjugated with N-acetylgalactosamine (GalNAc), thereby enhancing hepatocyte uptake via the asialoglycoprotein receptor (ASGPR). In comparison to GalNAc-ASO conjugation, clinical research indicates that unconjugated ASO is more effective in reducing hepatitis B virus surface antigen level. Recent studies have revealed that human sodium taurocholate co-transporting polypeptide (NTCP) is a functional cellular receptor for hepatitis B virus (HBV), and the bivalent bile acid structure may interact with multiple binding sites on NTCP, yielding much stronger interaction and substantially improved binding affinity. In this study, we synthesized NTCP ligand-antisense oligonucleotide (ASO) conjugation and evaluated the potential of antiviral therapy specifically reduction of HBV antigenemia in mice in vivo.