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Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731
- Source :
- Antimicrobial Agents and Chemotherapy
- Publication Year :
- 2020
-
Abstract
- 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).<br />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 EC50s from 1.84 μM to 7.3 μM. 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.
- Subjects :
- Hepatitis B virus
pgRNA packaging
medicine.disease_cause
Virus Replication
Antiviral Agents
03 medical and health sciences
Hepatitis B, Chronic
Cp
core protein
medicine
capsid
Humans
Pharmacology (medical)
core inhibitor
030304 developmental biology
Pharmacology
0303 health sciences
030306 microbiology
Chemistry
Viral Core Proteins
DNA replication
cccDNA
Entecavir
Hepatitis C, Chronic
Hepatitis B
Virology
body regions
Infectious Diseases
Capsid
Mechanism of action
Cell culture
DNA, Viral
medicine.symptom
DNA, Circular
pregenomic RNA
Nucleoside
medicine.drug
Subjects
Details
- ISSN :
- 10986596
- Volume :
- 64
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....d9db7bb553adf713ac1a456222ee9850