Novel NTCP ligand Dimeric Bile Acid Conjugated with ASO Reduce Hepatitis B Virus Surface Antigen in Vivo

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-10-10 DOI:10.1016/j.ejmech.2024.116955

Lei Lu, Dezi Cong, Tinghong Lv, Haisheng Wang, Xiaolei Wang

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引用次数: 0

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.

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与 ASO 共轭的新型 NTCP 配体二聚胆汁酸可降低体内乙型肝炎病毒表面抗原的含量

乙型肝炎病毒（HBV）会特异性地感染肝细胞，导致严重的肝病。然而，目前的治疗方法很少能达到功能性治愈。反义寡核苷酸（ASO）靶向前基因组 RNA，以减少乙型肝炎病毒（HBV）抗原的产生和病毒的复制，已被研究为治愈 HBV 的一种新型治疗策略，它可以与 N-乙酰半乳糖胺（GalNAc）共轭，从而通过 Asialoglycoprotein 受体（ASGPR）增强肝细胞的吸收。临床研究表明，与 GalNAc-ASO 共轭相比，非共轭 ASO 能更有效地降低乙型肝炎病毒表面抗原水平。最近的研究发现，人牛磺胆酸钠共转运多肽（NTCP）是乙型肝炎病毒（HBV）的功能性细胞受体，二价胆汁酸结构可能与 NTCP 上的多个结合位点相互作用，产生更强的相互作用，大大提高结合亲和力。在这项研究中，我们合成了 NTCP 配体-反义寡核苷酸（ASO）共轭物，并评估了其抗病毒治疗的潜力，特别是降低小鼠体内 HBV 抗原血症的潜力。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.