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Spectrochimica Acta. Part A, Molecular... Jul 2024Simeprevir and daclatasvir represent a cornerstone in the management of Hepatitis C Virus infection, a global health concern that affects millions of people worldwide....
Simeprevir and daclatasvir represent a cornerstone in the management of Hepatitis C Virus infection, a global health concern that affects millions of people worldwide. In this study, we propose a synergistic approach combining synchronous spectrofluorimetry and chemometric modeling i.e. Partial Least Squares (PLS-1) for the analysis of simeprevir and daclatasvir in different matrices. Moreover, the study employs firefly algorithms to further optimize the chemometric models via selecting the most informative features thus improving the accuracy and robustness of the calibration models. The firefly algorithm was able to reduce the number of selected wavelengths to 47-44% for simeprevir and daclatasvir, respectively offering a fast and sensitive technique for the determination of simeprevir and daclatasvir. Validation results underscore the models' effectiveness, as evidenced by recovery rates close to 100% with relative root mean square error of prediction (RRMSEP) of 2.253 and 2.1381 for simeprevir and daclatasvir, respectively. Moreover, the proposed models have been applied to determine the pharmacokinetics of simeprevir and daclatasvir, providing valuable insights into their distribution and elimination patterns. Overall, the study demonstrates the effectiveness of synchronous spectrofluorimetry coupled with multivariate calibration optimized by firefly algorithms in accurately determining and quantifying simeprevir and daclatasvir in HCV antiviral treatment, offering potential applications in pharmaceutical formulation analysis and pharmacokinetic studies for these drugs.
Topics: Imidazoles; Valine; Simeprevir; Pyrrolidines; Carbamates; Least-Squares Analysis; Spectrometry, Fluorescence; Algorithms; Antiviral Agents; Reproducibility of Results
PubMed: 38581722
DOI: 10.1016/j.saa.2024.124245 -
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 -
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 -
Fundamental & Clinical Pharmacology Jun 2024While the world is still facing the global pandemic COVID-19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the... (Review)
Review
BACKGROUND
While the world is still facing the global pandemic COVID-19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection.
OBJECTIVES
To get insight into the current treatment and prevention strategies will aid in effectively coping with the disease.
METHODS
For obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site.
RESULTS
There are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used-known as brincidofovir-which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in-vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In-silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV.
CONCLUSION
This review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.
Topics: Humans; Antiviral Agents; Mpox (monkeypox); Animals; Monkeypox virus
PubMed: 38226405
DOI: 10.1111/fcp.12980 -
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 -
Nature Communications Nov 2023Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest...
Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components. Here we describe a CID module based on the orally available, approved, small molecule simeprevir and its target, the NS3/4A protease from hepatitis C virus. We demonstrate the utility of this CID module as a molecular switch to control biological processes such as gene expression and apoptosis in vitro, and show that the CID system can be used to rapidly induce apoptosis in tumor cells in a xenograft mouse model, leading to complete tumor regression.
Topics: Humans; Mice; Animals; Simeprevir; Hepatitis C; Hepacivirus; Genetic Therapy; Apoptosis; Antiviral Agents; Viral Nonstructural Proteins
PubMed: 38012128
DOI: 10.1038/s41467-023-43484-9 -
AMB Express Nov 2023Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly...
Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection.
PubMed: 37917339
DOI: 10.1186/s13568-023-01634-8 -
Diagnostics (Basel, Switzerland) Sep 2023Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV...
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 ( = 9) and genotype 5 ( = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
PubMed: 37835845
DOI: 10.3390/diagnostics13193102 -
Cell Research Dec 2023Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including...
Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.
Topics: Humans; Biological Transport; Cryoelectron Microscopy; Liver; Liver-Specific Organic Anion Transporter 1; Organic Anion Transporters; Thyroid Hormones
PubMed: 37674011
DOI: 10.1038/s41422-023-00870-8