Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

Huang Qi; Cai Dawei; Yan RanLi LichunZong YuhuaGuo LidaMercier AlexandreZhou YiTang ArielHenne KirkColonno Richard

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Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

机译：Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

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ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC(50)s from 1.84 mu M to 7.3 mu M. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.

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《Antimicrobial agents and chemotherapy.》 |2020年第11期|共18页
作者
Huang Qi; Cai Dawei; Yan RanLi LichunZong YuhuaGuo LidaMercier AlexandreZhou YiTang ArielHenne KirkColonno Richard;
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作者单位

Assembly Biosci, San Francisco, CA 94080 USA;

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原文格式 PDF
正文语种英语
中图分类治疗学;
关键词
core protein; Cp; core inhibitor; cccDNA; hepatitis B virus; pregenomic RNA; antiviral agents; capsid; pgRNA packaging;

Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731

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