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Journal of Biomolecular Structure &... 2022The worldwide rapid spread of the COVID-19 disease necessitates the search for fast and effective treatments. The repurposing of existing drugs seems to be the best...
Combined use of the hepatitis C drugs and amentoflavone could interfere with binding of the spike glycoprotein of SARS-CoV-2 to ACE2: the results of a molecular simulation study.
The worldwide rapid spread of the COVID-19 disease necessitates the search for fast and effective treatments. The repurposing of existing drugs seems to be the best solution in this situation. In this study, the molecular docking method was used to test 248 drugs against the receptor-binding domain (RBD) of spike glycoprotein of SARS-CoV-2, which is responsible for viral entry into the host cell. Among the top-ranked ligands are drugs that are used for hepatitis C virus (HCV) treatments (paritaprevir, ledipasvir, simeprevir) and a natural biflavonoid amentoflavone. The binding sites of the HCV drugs and amentoflavone are different. Therefore, the ternary complexes of the HCV drug, amentoflavone, and RBD can be created. For the 5 top-ranked ligands, the validating molecular dynamics simulations of binary and ternary complexes with RBD were performed. According to the MMPBSA-binding free energies, the HCV drugs ledipasvir and paritaprevir (in a neutral form) are the most efficient binders of the RBD when used in combination with amentoflavone.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Molecular Docking Simulation; Hepacivirus; COVID-19; Peptidyl-Dipeptidase A; Protein Domains; Protein Binding; Molecular Dynamics Simulation; Hepatitis C; Glycoproteins
PubMed: 33896392
DOI: 10.1080/07391102.2021.1914168 -
Virus Research Jan 2021The resistance of hepatitis C virus (HCV) to direct-acting antiviral agents, used in chronic hepatitis C treatment, consists of a natural process resulting from... (Observational Study)
Observational Study
The resistance of hepatitis C virus (HCV) to direct-acting antiviral agents, used in chronic hepatitis C treatment, consists of a natural process resulting from resistance-associated substitutions (RASs) at specific amino acid regions. To identify and establish the natural prevalence of RASs in the NS3 gene in patients with chronic hepatitis C in the state of Pará, northern Brazil. Molecular analysis was performed on a total of 35 patients infected with HCV genotype 1, who were treatment-naive to protease inhibitors. HCV RNA was extracted from plasma and the NS3 region was amplified and submitted to DNA sequencing (Sanger). The general natural prevalence of RASs in the NS3 gene was 37.5 % (Y56F and S122T). The substitutions Y56F (34.3 %), S122T (3.1 %), V132I (15.6 %) and V170I (9.3 %) were identified. Y56F and S122T provide resistance to the protease inhibitors grazoprevir and simeprevir, respectively. All amino acid substitutions in the NS3 gene, including RASs, identified in patients from the state of Pará were present in other Brazilian studies. The natural presence of RASs in this study reflects the elevated genetic variability of HCV.
Topics: Adult; Aged; Amino Acid Substitution; Antiviral Agents; Brazil; Drug Resistance, Viral; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Mutation, Missense; Prospective Studies; Protease Inhibitors; Viral Nonstructural Proteins
PubMed: 33259871
DOI: 10.1016/j.virusres.2020.198251 -
The Journal of General Virology Feb 2022Drug resistance mutations of hepatitis C virus (HCV) negatively impact viral replicative fitness. RNA viruses are known to change their replication behaviour when...
Drug resistance mutations of hepatitis C virus (HCV) negatively impact viral replicative fitness. RNA viruses are known to change their replication behaviour when subjected to suboptimal selection pressure. Here, we assess whether mutation supply in HCV is sufficiently large to allow the selection of its variants during dual or triple direct-acting antiviral (DAA) treatment associated with augmented virus fitness or impairment. We engineered randomly mutagenized full-genome libraries to create a highly diverse population of replication-competent HCV variants in cell culture. These variants exhibited escape when treated with NS5A/NS5B inhibitors (daclatasvir/sofosbuvir), and relapse on treatment with a combination of NS3/NS5A/NS5B inhibitors (simeprevir or paritaprevir/daclatasvir/sofosbuvir). Analysis of the relationship between virus fitness and drug resistance of JFH1-derived NS5A-5B variants showed a significant positive correlation (=0.003). At the earliest time points, intracellular RNA levels remain unchanged in both the subgenomic replicon and infection assays, whereas extracellular RNA levels increased upto ten-fold compared to wild-type JFH1. Beneficial substitutions hyperstimulated phosphatidylinositol 4-phosphate during DAA treatment, and showed decreased dependence on cyclophilins during cyclosporine A treatment, indicating an interplay of virus-host molecular mechanisms in beneficial substitution selection that may necessitate infectious virus production. This comprehensive study demonstrates a possible role for HCV fitness of overcoming drug-mediated selection pressure.
Topics: Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans
PubMed: 35133954
DOI: 10.1099/jgv.0.001699 -
PloS One 2020Chronic Hepatitis C Virus (HCV) infection is still a major health issue especially in endemic areas where fewer direct-acting virals (DAAs) are treatment options. Some...
Chronic Hepatitis C Virus (HCV) infection is still a major health issue especially in endemic areas where fewer direct-acting virals (DAAs) are treatment options. Some HCV variants are associated with resistance and it reduces DAAs success where pre-existing variants prevail. In this study, we investigated resistance-associated polymorphisms (RAPs) in the HCV NS3 region from DAAs naïve Pakistani patients. 277 chronic HCV treatment naïve patients infected with genotype 1a, 3a and 3b were selected from various clinical centers in the capital city of Khyber Pakhtunkhwa province Pakistan. All the patients were included in this study after taking informed consent. HCV NS3 region was amplified and Sanger sequencing was performed to analyze RAPs to NS3 protease inhibitors. Of the total 29.24% (81/277) patients had detected with known RAPs viz V36A/G/L, T54S, V55A/D/I, Q80K/R, S122G/T/R, R155K/T/I, V158I, D168T/Q, and I170V. Among HCV-1a subjects overall RAPs found were 26.09% (12/46) and most prevalent substitutions were V36A/G (10.87%, 5/46) and R155K/T/I (8.70%, 4/46). Of the total HCV-3a infected patients, 30.95% were observed with RAPS. Ammon these, the most frequent substitutions were Q80R (13.69%, 23/168) followed by V36L (18.33%, 14/168) and V55I (5.95%, 10/168). Among HCV-3b patients, 26.98% were found with RAPs and S122R and Q80R were the dominant variants detected in 17.46 (11/63) and 12.70% (8/63) patients respectively. All these substitutions were associated with Boceprevir, Simeprevir, Telaprevir, and Paritaprevir. Single substitution in one sequence was found in 18.77% (52/277) and multiple in 10.46% (29/277). More than one RAP was frequent in HCV-3a sequences. Natural RAPs are common in chronic HCV patients infected with genotype 1a, 3a and 3b, the most prevalent subtypes in Pakistan. High prevalence of HCV NS3 RAPs suggested a large scale study of the NS3 gene before the introduction of NS3 protease inhibitors in Pakistan.
Topics: Adult; Antiviral Agents; Drug Resistance, Viral; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Pakistan; Polymorphism, Genetic; Sequence Analysis, DNA; Viral Nonstructural Proteins
PubMed: 32275694
DOI: 10.1371/journal.pone.0231480 -
Value in Health Regional Issues Dec 2020To introduce and discuss the cost and effectiveness of using sofosbuvir, daclatasvir, and simeprevir antivirals, in combination or not with peginterferon alfa and...
OBJECTIVES
To introduce and discuss the cost and effectiveness of using sofosbuvir, daclatasvir, and simeprevir antivirals, in combination or not with peginterferon alfa and ribavirin, for the treatment of hepatitis C, as based on real-world data.
METHODS
We analyzed the treatment and outcomes of 253 patients from a retrospective cohort held in a specialized assistance service in the municipality of Porto Alegre, Brazil. Regarding costs, we considered only the direct costs of the antiviral medications per unit (pills), according to the financial receipts of the public procurements. We calculated the total cost of treatment per individual and the cost per cure expressed in sustained virologic response (SVR).
RESULTS
Most patients (66.8%) were carriers of the genotype 1 of hepatitis, and 92.9% reached the SVR. The average cost of the treatment for genotype-1 patients was $5,862.31 USD per patient and $6,310.34 for the cure; for genotype-3 patients, on the other hand, the cost was $5,144.27 per patient and $5,974.76 for the cure. The drugs purchasing cost was around 40% less than was estimated for the process of incorporating them into the public health system.
CONCLUSION
The results indicated that good rates of effectiveness were achieved with different combinations of the medicines. The costs of the medicines were still deemed too high for the Brazilian reality, however. Therefore the results contribute to support the formulation and review of public policies based on strong evidence and on real-world data for the treatment of hepatitis C.
Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Brazil; Cohort Studies; Cost-Benefit Analysis; Female; Health Care Costs; Hepatitis C, Chronic; Humans; Male; Middle Aged; Retrospective Studies
PubMed: 32702649
DOI: 10.1016/j.vhri.2020.05.002 -
Fungal Biology May 2021Candida haemulonii species complex (C. haemulonii, C. haemulonii var. vulnera and Candida duobushaemulonii) is composed by emerging and multidrug-resistant (MDR)...
Candida haemulonii species complex (C. haemulonii, C. haemulonii var. vulnera and Candida duobushaemulonii) is composed by emerging and multidrug-resistant (MDR) yeasts. Candidiasis, the disease caused by these species, is difficult to treat and culminates in clinical failures and patient death. It is well-known that Candida peptidases play important roles in the fungus-host interactions, and hence these enzymes are promising targets for developing new antifungal drugs. Recently, serine-type peptidases were described in clinical isolates of C. haemulonii complex with the ability to cleave relevant key host proteins. Herein, the effects of serine peptidase inhibitors (SPIs) on the cell biology of this fungal complex were evaluated. Initially, eight distinct SPIs (phenylmethylsulfonyl fluoride - PMSF, 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride - AEBSF, N-α-tosyl-l-lysine chloromethyl ketone hydrochloride - TLCK, N-p-tosyl-l-phenylalanine chloromethyl ketone - TPCK, simeprevir, boceprevir, danoprevir and telaprevir) were tested on the fungal growth. TPCK showed the best efficacy in controlling cell proliferation, being selected for the following experiments. This SPI induced changes in the architecture of yeast cells, as observed by scanning electron microscopy, besides injuries at the plasma membrane and reduction in the ergosterol content. TPCK also diminished the ability of yeasts to adhere to abiotic (polystyrene and glass) and biotic (murine macrophages) surfaces in a typically concentration-dependent manner. In addition, the 24 h-treatment of the mature biofilm promoted a decrease in biomass, viability and extracellular matrix. Altogether, our results highlight that SPIs may be promising new therapeutic agents in the treatment of candidiasis caused by emergent, opportunistic and MDR species forming the C. haemulonii complex.
Topics: Animals; Candida; Mice; Phenylalanine; Protease Inhibitors; Serine; Tosylphenylalanyl Chloromethyl Ketone
PubMed: 33910679
DOI: 10.1016/j.funbio.2020.12.004 -
The Egyptian Journal of Internal... 2023Hepatitis C is associated with metabolic effects and fatty liver disease. The effect of different direct antivirals on the liver steatosis, and the metabolic profile,...
BACKGROUND
Hepatitis C is associated with metabolic effects and fatty liver disease. The effect of different direct antivirals on the liver steatosis, and the metabolic profile, still needs to be established. The aim of this study is to determine the effect of achieving the sustained virological response after 12 weeks (SVR-12 weeks) with different combinations of direct antiviral drugs, on the hepatic steatosis, and fibrosis presented by laboratory and transient elastography parameters. Our study population is nondiabetic, chronically infected HCV Egyptian patients and naïve to any form of HCV treatment.
METHODS
This cohort study was carried on 100 nondiabetic HCV treatment-naïve patients attending the Hepatology Clinic, in the Gastroenterology and Hepatology Department, Ain Shams University, and Kobry El Koba Military Hospital. The patients were divided into four groups according to their treatment regimens as follows: group A: 25 patients who received sofosbuvir (400 mg) and daclatasvir (60 mg) daily for 12 weeks; group B: 25 patients who received sofosbuvir (400 mg) and ledipasvir (90 mg) daily for 12 weeks; group C: 25 patients who received ombitasvir (12.5 mg), paritaprevir (75 mg), and ritonavir (50 mg) daily for 12 weeks; and group D: 25 patients who received sofosbuvir (400 mg) and simeprevir (150 mg) daily for 12 weeks. All patients were subjected to the following investigations: HCV quantitative PCR before and after 12 weeks of treatment, clinical and laboratory metabolic evaluation including alfa-fetoprotein level, thyroid profile assessment, ferritin level, pelvi-abdominal ultrasound, and FibroScan examination.
RESULTS
All patients achieved SVR after 12 weeks. FibroScan median decreased ( < 0.001) from 19.29 ± 6.97 kPa at baseline to 14.15 ± 6.48 kPa at SVR12. NAFLD score median increased from 1.88 (1.49-2.22) at baseline to 2.01 (1.61-2.33) after 12 weeks of treatment. The highest level of NAFLD score was in group C, and the lowest was in group B. The BMI mean decreased from 28.31 ± 1.53 at baseline to 28.07 ± 1.52 at SVR12. HbA1C level mean decreased from 5.73 ± 0.23 at baseline to 5.40 ± 0.24 at SVR12. In addition, liver enzymes, cholesterol, triglycerides, APRI score (AST-platelet ratio index), and HBA1C decreased after 12-week treatment with a statistically significant difference, while the mean LDL increased after 12 weeks of treatment.
CONCLUSIONS
DAAs affect the metabolic profile of the treated patients. There is a noticed improvement in the FibroScan, NAFLD score, and lipid profile after achieving the SVR-12 weeks. However, LDL is increased after viral cure, mostly due to viral-host molecular interaction.
PubMed: 36816629
DOI: 10.1186/s43162-023-00197-1 -
Global Health & Medicine Aug 2022It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of...
It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, = 320) or Sim+IFN (000015933, = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.
PubMed: 36119787
DOI: 10.35772/ghm.2022.01026 -
Journal of Biomolecular Structure &... Jan 2022The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for...
The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (), estimated inhibition constants (), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of -259.522 ± 17.579 and -154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Pharmaceutical Preparations; SARS-CoV-2
PubMed: 32885740
DOI: 10.1080/07391102.2020.1814870 -
Journal of Medical Case Reports Nov 2021In recent years, numerous studies have reported the development or exacerbation of sarcoidosis due to interferon therapy. However, ocular lesions rarely present as... (Review)
Review
BACKGROUND
In recent years, numerous studies have reported the development or exacerbation of sarcoidosis due to interferon therapy. However, ocular lesions rarely present as initial symptoms. Herein, we describe a rare case of interferon-α-induced sarcoidosis with uveitis as the initial symptom, and present a review of the relevant literature.
CASE PRESENTATION
This case involved a 62-year-old-Japanese woman with a history of a combination treatment of pegylated interferon-α-2a, ribavirin, and simeprevir, after which she developed granulomatous panuveitis. She was subsequently diagnosed with sarcoidosis following histological examination of skin biopsy specimens. In addition to reporting this case, we performed a literature review of 27 cases (24 case reports) of histopathologically diagnosed interferon-α-induced sarcoidosis published between January 2009 and November 2018.
CONCLUSIONS
Among the reviewed cases, 23 (85.1%) cases developed skin lesions and 19 (70.1%) had lung lesions. Only three cases (11.1%) had accompanying eye lesions. Interferon-α therapy was discontinued in 16 cases (52.9%), and the majority exhibited improvement after systemic corticosteroid treatment. There are few reported cases of interferon-α-induced sarcoidosis with uveitis as the initial symptom. However, if uveitis develops during or after interferon-α treatment, it might represent an initial symptom of interferon-α-induced sarcoidosis, as observed in the present case.
Topics: Antiviral Agents; Female; Humans; Middle Aged; Panuveitis; Ribavirin; Sarcoidosis; Uveitis
PubMed: 34836557
DOI: 10.1186/s13256-021-03181-x