Identification of a novel long-acting 4'-modified nucleoside reverse transcriptase inhibitor against HBV.
Animals
Delayed-Action Preparations
/ pharmacology
Disease Models, Animal
Drug Administration Routes
Drug Administration Schedule
Drug Development
/ methods
Drug Resistance, Viral
/ drug effects
Hepatitis B
/ drug therapy
Hepatitis B virus
/ drug effects
Humans
Mice
RNA-Directed DNA Polymerase
/ metabolism
Reverse Transcriptase Inhibitors
/ pharmacology
Time
Drug-resistant HBVs
HBV
Human-liver-chimeric mice
Long-acting anti-HBV therapeutic
NRTI
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
30
03
2020
revised:
05
11
2020
accepted:
01
12
2020
pubmed:
18
12
2020
medline:
1
2
2022
entrez:
17
12
2020
Statut:
ppublish
Résumé
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. 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. E-CFCP potently blocked HBV E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV. 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.
Sections du résumé
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 HBV
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.
Identifiants
pubmed: 33333207
pii: S0168-8278(20)33843-5
doi: 10.1016/j.jhep.2020.12.006
pmc: PMC9703152
mid: NIHMS1685647
pii:
doi:
Substances chimiques
Delayed-Action Preparations
0
Reverse Transcriptase Inhibitors
0
RNA-Directed DNA Polymerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1075-1086Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011486
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Conflict of interest Yasuhito Tanaka has received personal fees from Fujirebio Inc. Except for Yasuhito Tanaka, none of the co-authors has issues to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.
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