Back to Search
Start Over
Identification of a novel long-acting 4’-modified nucleoside reverse transcriptase inhibitor against HBV
- Source :
- J Hepatol
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Background & Aims While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence of NRTI-resistant HBV variants is an issue because of the requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes. Methods Herein, we synthesized a novel long-acting 4’-modified NRTI termed E-CFCP. We tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP’s long-acting features and E-CFCP-triphosphate’s interactions with the HBV reverse transcriptase (HBV-RT) were examined. Results E-CFCP potently blocked HBVWTD1 production (IC50qPCR_cell=1.8 nM) in HepG2.2.15 cells and HBVWTC2 (IC50SB_cell=0.7 nM), entecavir (ETV)-resistant HBVETV-RL180M/S202G/M204V (IC50SB_cell=77.5 nM), and adefovir-resistant HBVADV-RA181T/N236T production (IC50SB_cell=14.1 nM) in Huh7 cells. E-CFCP profoundly inhibited intracellular HBV DNA production to below the detection limit, but ETV and tenofovir alafenamide (TAF) failed to do so. E-CFCP also showed less toxicity than ETV and TAF. E-CFCP better penetrated hepatocytes and was better tri-phosphorylated; E-CFCP-triphosphate persisted intracellularly for longer than ETV-triphosphate. Once-daily peroral E-CFCP administration over 2 weeks (0.02~0.2 mg/kg/day) reduced HBVWTC2-viremia by 2–3 logs in PXB-mice without significant toxicities and the reduction persisted over 1–3 weeks following treatment cessation, suggesting once-weekly dosing capabilities. E-CFCP also reduced HBVETV-RL180M/S202G/M204V-viremia by 2 logs over 2 weeks, while ETV completely failed to reduce HBVETV-RL180M/S202G/M204V-viremia. E-CFCP’s 4’-cyano and fluorine interact with both HBVWT-RT and HBVETV-RL180M/S202G-M204 -RT via Van der Waals and polar forces, being important for E-CFCP-triphosphate’s interactions and anti-HBV potency. Conclusion E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV. Lay summary Although there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve outcomes and quality of life. Herein, we report preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible, which is preferrable to the current daily dosing regimens.
- Subjects :
- 0301 basic medicine
Hepatitis B virus
Cell
Pharmacology
Tenofovir alafenamide
Article
Drug Administration Schedule
Time
Mice
03 medical and health sciences
0302 clinical medicine
Drug Development
Drug Resistance, Viral
medicine
Animals
Humans
Potency
Hepatitis B e Antigens
Dosing
Hepatology
Reverse-transcriptase inhibitor
business.industry
Drug Administration Routes
virus diseases
RNA-Directed DNA Polymerase
Entecavir
Hepatitis B
Reverse transcriptase
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Delayed-Action Preparations
Toxicity
Reverse Transcriptase Inhibitors
030211 gastroenterology & hepatology
business
medicine.drug
Subjects
Details
- ISSN :
- 01688278
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Journal of Hepatology
- Accession number :
- edsair.doi.dedup.....4c07fba06f7992bb1a75a9133ebe59d2