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Journal of Molecular Graphics &... Mar 2021The methyl methanesulfonate and ultraviolet sensitive 81 (MUS81) is a structure-specific endonuclease that is highly conserved in eukaryotes and essential for homologous...
The methyl methanesulfonate and ultraviolet sensitive 81 (MUS81) is a structure-specific endonuclease that is highly conserved in eukaryotes and essential for homologous recombination repair. The winged-helix domain at the N-terminus of MUS81 (wMUS81) can bind DNA substrates and regulate the endonuclease activity. The repression of MUS81 activity could enhance the sensitivity to antitumor compounds of different tumour cells. Thus, MUS81 is a potential therapeutic target in cancer therapy. However, specific inhibitors of MUS81 have remained elusive. Here, for the first time, we attempt to discover the compounds disrupting the wMUS81 activity. The binding affinity of available drugs to wMUS81 was first estimated by molecular docking. pK values were taken into consideration to eliminate unlikely protonation states of the ligands. Top-lead compounds were then estimated the binding affinity using the fast pulling ligand simulations. Finally, the free energy perturbation method accurately defined the absolute binding free energy of the top four ligands, revealing the most potential inhibitors of wMUS81 including simeprevir and nilotinib. Binding of simeprevir destabilizes the β-hairpin region of wMUS81, likely disturbing the wMUS81 function. The van der Waals free binding energy majorly modulates the ligand-binding mechanism. The two conserved residues Leu189 and Arg196 are likely important in monitoring the interacting process of simeprevir to wMUS81.
Topics: DNA-Binding Proteins; Endonucleases; Methyl Methanesulfonate; Molecular Docking Simulation; Recombination, Genetic
PubMed: 33340918
DOI: 10.1016/j.jmgm.2020.107771 -
Antiviral Research Nov 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CL) of SARS-CoV-2 plays a...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CL) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this work, we have employed bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening inhibitors against SARS-CoV-2 3CL, and then applied the assay to screen a collection of known HIV/HCV protease inhibitors. Our results showed that the assay is capable of quantification of the cleavage efficiency of 3CL with good reproducibility (Z' factor is 0.59). Using the assay, we found that 9 of 26 protease inhibitors effectively inhibited the activity of SARS-CoV-2 3CL in a dose-dependent manner. Among them, four compounds exhibited the ability to bind to 3CLin vitro. HCV protease inhibitor simeprevir showed the most potency against 3CL with an EC vale of 2.6 μM, bound to the active site pocket of 3CL in a predicted model, and importantly, exhibited a similar activity against the protease containing the mutations P132H in Omicron variants. Taken together, this work demonstrates the feasibility of using the cell-based BRET assay for screening 3CL inhibitors and supports the potential of simeprevir for the development of 3CL inhibitors.
Topics: Antiviral Agents; Coronavirus 3C Proteases; Cysteine Endopeptidases; Drug Repositioning; HIV Infections; HIV Protease Inhibitors; Hepatitis C; Humans; Protease Inhibitors; Reproducibility of Results; SARS-CoV-2; Simeprevir; COVID-19 Drug Treatment
PubMed: 36155070
DOI: 10.1016/j.antiviral.2022.105419 -
Saudi Journal of Biological Sciences Apr 2021is a common enteric parasite, having a worldwide distribution. Many antimicrobial agents are effective against it, yet side effects and drug resistance have been...
INTRODUCTION AND AIM
is a common enteric parasite, having a worldwide distribution. Many antimicrobial agents are effective against it, yet side effects and drug resistance have been reported. Thus, ongoing trials are being conducted for exploring anti- alternatives. Proteases are attractive anti-protozoal drug targets, having documented roles in . Serine proteases are present in both hepatitis C virus and . Since drug repositioning is quite trendy, the efficacy of simeprevir (SMV), an anti-hepatitis serine protease inhibitor, against was investigated in the current study.
METHODS
Stool samples were collected from patients, Alexandria, Egypt. Concentrated stools were screened using direct smears, trichrome, and modified Ziehl-Neelsen stains to exclude parasitic co-infections. Positive stool isolates were cultivated, molecularly subtyped for assessing the efficacy of three SMV doses (100,150, and 200 μg/ml) along 72 hours (h), on the most common subtype, through monitoring parasite growth, viability, re-culture, and also via ultrastructure verification. The most efficient dose and duration were later tested on other subtypes.
RESULTS
Results revealed that was detected in 54.17% of examined samples. Molecularly, ST3 predominated (62%), followed by ST1 (8.6%) and ST2 (3.4%). Ascending concentrations of SMV progressively inhibited growth, viability, and re-culture of treated , with a non-statistically significant difference when compared to the therapeutic control metronidazole (MTZ). The most efficient dose and duration against ST3 was 150 µg/ml for 72 h. This dose inhibited the growth of ST3, ST1, and ST2 with percentages of 95.19%, 94.83%, and 94.74%, successively and viability with percentages of 98.30%, 98.09%, and 97.96%, successively. This dose abolished upon re-culturing. Ultra-structurally, SMV induced rupture of cell membrane leading to necrotic death, versus the reported apoptotic death caused by MTZ. In conclusion, 150 µg/ml SMV for 72 h proved its efficacy against ST1, ST2, and ST3 , thus sparing the need for pre-treatment molecular subtyping in developing countries.
PubMed: 33935570
DOI: 10.1016/j.sjbs.2021.01.050 -
PloS One 2021Comorbidities and comedication are common in patients with hepatitis C, which could result in a risk of drug-drug interaction. The objective of this study was to...
Direct antiviral agents for hepatitis C and drug interaction risk: A retrospective cohort study with real and simulated data on medication interaction, prevalence of comorbidities and comedications.
INTRODUCTION AND AIM
Comorbidities and comedication are common in patients with hepatitis C, which could result in a risk of drug-drug interaction. The objective of this study was to evaluate the prevalence of comorbidities, comedication and drug-drug interactions involving direct-acting antivirals in this population.
METHODS
Comorbidities and comedications were evaluated in a retrospective cohort of hepatitis C patients. Drug-drug interactions were estimated in real life and with simulated data on comedications following drug regimens: telaprevir; elbasvir/grazoprevir, ombitasvir/paritaprevir/r/ritonavir (2D regimen), and sofosbuvir/simeprevir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir; 2D/dasabuvir (3D regimen); glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir. The interactions were evaluated according to the University of Liverpool database. Statistical analysis was performed by SPSS® 18.0.
RESULTS
Data from 1433 patients with hepatitis C were evaluated. The mean patient age was 51.7 years (SD ± 10.7), and 50.6% were female. Direct-acting antivirals were prescribed for 345 (24.1%) patients, and a sustained virological response occurred in 264 (76.5%). The main comorbidities were systemic arterial hypertension [436 (30.4%)], diabetes mellitus [352 (24.6%)] and depression [130 (9.1%)]. The mean number of comorbidities was 1.52 (median [IQR] of 1.00 [1.00-2.00]). The mean number of comedications was 3.16 (median [IQR] of 3.00 [1.00-5.00]). A total of 12916 drug-drug interactions were found, of which 1.859 (14.4%) were high risk, with a mean of 1.29 ± 3.13 per patient. The 3D regimen, as well as glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir, presented the highest drug-drug interaction indexes.
CONCLUSION
Comorbidities and comedications are common in patients with hepatitis C, as are drug-drug interactions. Even when second generation drugs are used, the occurrence of drug-drug interactions still presents a significant risk.
Topics: Age Distribution; Antiviral Agents; Comorbidity; Drug Interactions; Female; Hepatitis C; Humans; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Factors
PubMed: 33577593
DOI: 10.1371/journal.pone.0245767 -
Bioorganic Chemistry Jan 2021Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the...
BACKGROUND
Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19.
METHODS
We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19.
RESULTS
Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole).
CONCLUSIONS
The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Computational Chemistry; Drug Discovery; Drug Repositioning; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33261845
DOI: 10.1016/j.bioorg.2020.104490 -
BMC Chemistry Jul 2023The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir...
Mathematical processing of absorption as green smart spectrophotometric methods for concurrent assay of hepatitis C antiviral drugs, Sofosbuvir and Simeprevir: application to combined pharmaceutical dosage forms and evaluation of the method greenness.
The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0-50.0 and 2.0-50.0 µg mL for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works.
PubMed: 37452429
DOI: 10.1186/s13065-023-00984-5 -
The Journal of General Virology Feb 2020To establish infectious genotype 4a (GT4a) cell culture-derived hepatitis C virus (HCVcc), we constructed full-length ED43 and 12 mutants possessing single or double...
To establish infectious genotype 4a (GT4a) cell culture-derived hepatitis C virus (HCVcc), we constructed full-length ED43 and 12 mutants possessing single or double mutations that increase ED43 replicon replication, and performed cell culture after RNA transfection. Sequential long-term culture of full-length ED43 RNA-transfected cells showed increased viral production in two ED43 mutants named ED43 QK/SI and TR/SI among the tested clones. These ED43 mutants possessed a common mutation, R1405G, in the NS3 helicase region and another mutation, D2413G or V2414A, in the NS5a-NS5b cleavage site. Furthermore, serial reinfection of naïve Huh7.5.1 cells accelerated peak HCV production at an earlier time point after every infection. After the fourth infection, we found a common mutation, R1405G, and six additional mutations in both ED43 QK/SI and TR/SI mutants. All seven mutations supported continuous viral production for more than 40 days in both ED43 QS-7M (QK/SI with seven mutations) and ED43 TS-7M (TR/SI with seven mutations). In addition, ED43 TS-7M did not require additional mutations for continuous virus culture up to 124 days. Both ED43 QS-7M and TS-7M were sensitive to the neutralizing E2 antibodies HCV1 and AR3A and the direct-acting antivirals, simeprevir, ledipasvir and sofosbuvir. In conclusion, we established an infectious ED43 strain containing adaptive mutations, which is important for the analysis of HCV genotype-specific pathogenesis, development of pan-genotypic agents and analysis of drug resistance.
Topics: Antibodies, Neutralizing; Antiviral Agents; Cell Culture Techniques; Cell Line; Genotype; Hepacivirus; Hepatitis C; Humans; Mutation; Replicon; Viral Nonstructural Proteins; Viral Proteins; Virus Replication
PubMed: 31859613
DOI: 10.1099/jgv.0.001378 -
Annals of Hepatology 2019Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil...
INTRODUCTION AND OBJECTIVES
Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil for treatment of hepatitis C virus (HCV) infection. The aims of this study were to assess effectiveness and safety of HCV treatment with DAA in real-life world in a highly admixed population from Brazil.
MATERIALS AND METHODS
All Brazilian reference centers for HCV treatment were invited to take part in a web-based registry, prospectively conducted by the Brazilian Society of Hepatology, to assess outcomes of HCV treatment in Brazil with DAAs. Data to be collected included demographics, disease severity and comorbidities, genotype (GT), viral load, DAA regimens, treatment side effects and sustained virological response (SVR).
RESULTS
3939 patients (60% males, mean age 58±10 years) throughout the country were evaluated. Most had advanced fibrosis or cirrhosis, GT1 and were treated with SOF/DCV or SOF/SIM. Overall SVR rates were higher than 95%. Subjects with decompensated cirrhosis, GT2 and GT3 have lower SVR rates of 85%, 90% and 91%, respectively. Cirrhosis and decompensated cirrhosis in GT1 and male sex and decompensated cirrhosis in GT3 were significantly associated with no SVR. Adverse events (AD) and serious AD occurred in 18% and 5% of those subjects, respectively, but less than 1% of patients required treatment discontinuation.
CONCLUSION
SOF-based DAA regimens are effective and safe in the heterogeneous highly admixed Brazilian population and could remain an option for HCV treatment at least in low-income countries.
Topics: Aged; Antiviral Agents; Brazil; Carbamates; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Prognosis; Prospective Studies; Pyrrolidines; Ribavirin; Sex Factors; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine
PubMed: 31537509
DOI: 10.1016/j.aohep.2019.08.001 -
Structural Chemistry 2020Presently, the SARS-CoV-2 (COVID-19) pandemic has been spreading throughout the world. Some drugs such as lopinavir, simeprevir, hydroxychloroquine, chloroquine, and...
Presently, the SARS-CoV-2 (COVID-19) pandemic has been spreading throughout the world. Some drugs such as lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir have been recommended for COVID-19 treatment by some researchers, but these drugs were not effective enough against this virus. This study based on in silico approaches was aimed to increase the anti-COVID-19 activities of these drugs by using caulerpin and its derivatives as an adjunct drug against SARS-CoV-2 receptor proteins: the SARS-CoV-2 main protease and the SARS-CoV-2 spike protein. Caulerpin exhibited antiviral activities against chikungunya virus and herpes simplex virus type 1. Caulerpin and some of its derivatives showed inhibitory activity against Alzheimer's disease. The web server ANCHOR revealed higher protein stability for the two receptors with disordered score (< 0.6). Molecular docking analysis showed that the binding energies of most of the caulerpin derivatives were higher than all the suggested drugs for the two receptors. Also, we deduced that inserting NH, halogen, and vinyl groups can increase the binding affinity of caulerpin toward 6VYB and 6LU7, while inserting an alkyl group decreases the binding affinity of caulerpin toward 6VYB and 6LU7. So, we can modify the inhibitory effect of caulerpin against 6VYB and 6LU7 by inserting NH, halogen, and vinyl groups. Based on the protein disordered results, the SARS-CoV-2 main protease and SARS-CoV-2 spike protein domain are highly stable proteins, so it is quite difficult to unstabilize their integrity by using individual drugs. Also, molecular dynamics (MD) simulation indicates that binding of the combination therapy of simeprevir and the candidate studied compounds to the receptors was stable and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. So, this study suggested that caulerpin and its derivatives could be used as a combination therapy along with lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir for disrupting the stability of SARS-CoV2 receptor proteins to increase the antiviral activity of these drugs.
PubMed: 32837118
DOI: 10.1007/s11224-020-01586-w -
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