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F1000Research 2022Medicinal plants are potential resources for isolating drug candidates. Various plants have been reported to possess pharmacological effects including anti-hepatitis C...
Medicinal plants are potential resources for isolating drug candidates. Various plants have been reported to possess pharmacological effects including anti-hepatitis C activities. The current study examined the anti-hepatitis C virus (HCV) activities of extracts in solvents with various polarities and further evaluated the mechanism of action of the extracts using Western blotting and combination treatment models. The leaves of were extracted in two phases, first in ethanol and then in solvents with different polarities (n-hexane, dichloromethane, and methanol). HCV-infected Huh7it-1 cells were treated with the extracts at concentrations of 0.01, 0.1, 1, 10, 50, and 100 µg/mL. The results revealed the strong anti-HCV activities of the extracts. The 50% inhibition concentrations (IC s) of the ethanol, n-hexane, dichloromethane and methanol extracts were of 4.6 ± 0.3, 2.9 ± 0.2, 0.2 ± 0.3, and 2.8 ± 0.2 μg/mL, respectively, and no cytotoxic effect was detected. These extracts displayed stronger effects than the positive control ribavirin. The mode of action of the ethanol extract was evaluated at 30 µg/mL, revealing that the inhibitory effect was stronger on the post-entry step than on the entry step. Western blotting revealed that the extracts decreased NS3 protein expression, indicating that virus replication was suppressed. Further evaluation illustrated that combined treatment with the ethanol extract enhanced the anti-viral activity of simeprevir. These results indicated that leaves could represent sources of anti-HCV agents.
Topics: Plant Extracts; Acacia; Hepacivirus; Methanol; Methylene Chloride; Solvents; Hepatitis C; Ethanol
PubMed: 38046541
DOI: 10.12688/f1000research.124947.3 -
Drug Metabolism and Disposition: the... May 2024The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While...
The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 M. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 M, which is physiologically relevant in comparison with the K of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 M). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC ∼twofold from 11 M to 5 M. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K and K values of 4.66 M and 0.00954 minute, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.
Topics: Humans; Cytochrome P-450 CYP3A; Female; Antiviral Agents; Pregnancy; Oxidation-Reduction; Dehydroepiandrosterone Sulfate; Hepacivirus; Hepatitis C; Cytochrome P-450 CYP3A Inhibitors; Maternal-Fetal Exchange; Microsomes, Liver; Fetus
PubMed: 38267095
DOI: 10.1124/dmd.123.001434 -
Journal of Biomolecular Structure &... Jul 2023In the pursuit of developing novel anti-leishmanial agents, we conducted an extensive computational study to screen inhibitors from the FDA-approved ZINC database...
In the pursuit of developing novel anti-leishmanial agents, we conducted an extensive computational study to screen inhibitors from the FDA-approved ZINC database against glutathione synthetase. The three-dimensional structure of glutathione synthetase was constructed by homology modeling, using the crystallographic structure of glutathione synthetase as a template. Subsequently, molecular docking studies were carried out for a large number of compounds using AutoDock Vina. Among the screened compounds, we selected the top five with strong binding affinity to glutathione synthetase but having a very low affinity to its human homolog. Further investigations on protein-ligand complexes were done by conducting molecular dynamics (MD) simulation and MM/PBSA analysis. The results revealed that Olysio (Simeprevir) exhibited the lowest binding energy (-89.21 kcal/mol), followed by Telithromycin (-45.34 kcal/mol). These findings showed that these compounds have the potential to act as inhibitors of glutathione synthetase. Hence, our study provides valuable insights for the development of a novel therapeutic strategy against by targeting the glutathione synthetase enzyme.Communicated by Ramaswamy H. Sarma.
PubMed: 37491862
DOI: 10.1080/07391102.2023.2240429 -
Archives of Virology Feb 2024
Retraction Note: High success rates for the use of sofosbuvir/ombitasvir/paritaprevir/ritonavir + ribavirin and sofosbuvir/simeprevir/daclatasvir + ribavirin in retreatment of chronic hepatitis C infection after unsuccessful sofosbuvir/daclatasvir therapy: a real-life experience.
PubMed: 38349452
DOI: 10.1007/s00705-024-05990-z