Furanocoumarins promote proteasomal degradation of viral HBx protein and down-regulate cccDNA transcription and replication of hepatitis B virus
Copyright © 2024 Elsevier Inc. All rights reserved..
Nucleot(s)ide analogues, the current antiviral treatments against chronic hepatitis B (CHB) infection, are non-curative due to their inability to eliminate covalently closed circular DNA (cccDNA) from the infected hepatocytes. Preclinical studies have shown that coumarin derivatives can effectively reduce the HBV DNA replication. We evaluated the antiviral efficacy of thirty new coumarin derivatives in cell culture models for studying HBV. Furanocoumarins Fc-20 and Fc-31 suppressed the levels of pre-genomic RNA as well as cccDNA, and reduced the secretion of virions, HBsAg and HBeAg. The antiviral efficacies of Fc-20 and Fc31 improved further when used in combination with the hepatitis B antiviral drug Entecavir. There was a marked reduction in the intracellular HBx level in the presence of these furanocoumarins due to proteasomal degradation resulting in the down-regulation of HBx-dependent viral genes. Importantly, both Fc-20 and Fc-31 were non-cytotoxic to cells even at high concentrations. Further, our molecular docking studies confirmed a moderate to high affinity interaction between furanocoumarins and viral HBx via residues Ala3, Arg26 and Lys140. These data suggest that furanocoumarins could be developed as a new therapeutic for CHB infection.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:595 |
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| Enthalten in: |
Virology - 595(2024) vom: 24. März, Seite 110065 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tyagi, Purnima [VerfasserIn] |
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| Links: |
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| Themen: |
3.5 Kb RNA |
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| Anmerkungen: |
Date Revised 03.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.virol.2024.110065 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370586549 |
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| 520 | |a Copyright © 2024 Elsevier Inc. All rights reserved. | ||
| 520 | |a Nucleot(s)ide analogues, the current antiviral treatments against chronic hepatitis B (CHB) infection, are non-curative due to their inability to eliminate covalently closed circular DNA (cccDNA) from the infected hepatocytes. Preclinical studies have shown that coumarin derivatives can effectively reduce the HBV DNA replication. We evaluated the antiviral efficacy of thirty new coumarin derivatives in cell culture models for studying HBV. Furanocoumarins Fc-20 and Fc-31 suppressed the levels of pre-genomic RNA as well as cccDNA, and reduced the secretion of virions, HBsAg and HBeAg. The antiviral efficacies of Fc-20 and Fc31 improved further when used in combination with the hepatitis B antiviral drug Entecavir. There was a marked reduction in the intracellular HBx level in the presence of these furanocoumarins due to proteasomal degradation resulting in the down-regulation of HBx-dependent viral genes. Importantly, both Fc-20 and Fc-31 were non-cytotoxic to cells even at high concentrations. Further, our molecular docking studies confirmed a moderate to high affinity interaction between furanocoumarins and viral HBx via residues Ala3, Arg26 and Lys140. These data suggest that furanocoumarins could be developed as a new therapeutic for CHB infection | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CYEI mutant | |
| 650 | 4 | |a Coumarin derivatives | |
| 650 | 4 | |a Cyclin D1 promoter | |
| 650 | 4 | |a Furanocoumarin | |
| 650 | 4 | |a HBV replication | |
| 650 | 4 | |a HBx protein | |
| 650 | 4 | |a cccDNA | |
| 700 | 1 | |a Singh, Ankita |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Jitendra |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmad, Belal |e verfasserin |4 aut | |
| 700 | 1 | |a Bahuguna, Aparna |e verfasserin |4 aut | |
| 700 | 1 | |a Vivekanandan, Perumal |e verfasserin |4 aut | |
| 700 | 1 | |a Sarin, Shiv Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Vijay |e verfasserin |4 aut | |
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