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Cureus Jul 2021Hepatitis C is a ribonucleic acid (RNA) virus, and its presence in individuals was previously considered to be a chronic condition. However, recent therapeutic advances...
Hepatitis C is a ribonucleic acid (RNA) virus, and its presence in individuals was previously considered to be a chronic condition. However, recent therapeutic advances with virus-directed treatment have resulted in a significant increase in cure rates as demonstrated by an absence of virus on repeat testing. Currently, several individual and combination antiviral therapies are available for the treatment of hepatitis C virus infection. However, each of the hepatitis C antiviral agents is associated with potential adverse skin effects whose incidence varies depending on the agent used for treatment. The cutaneous reactions, including photosensitivity, usually resolve once the antiviral treatment is completed. In this report, we discuss the case of a chronic hepatitis C patient who developed sofosbuvir-velpatasvir (Epclusa)-associated toxicity, while receiving the antiviral therapy. The 57-year-old man developed cutaneous phototoxicity when he started treatment with the drug. The adverse skin reaction promptly resolved once the treatment was completed. Clinicians who manage patients being treated with antiviral agents for hepatitis C infection should consider counseling these individuals regarding photoprotection including avoidance of sun exposure, daily sunscreen use, and wearing photoprotective clothing.
PubMed: 34430111
DOI: 10.7759/cureus.16496 -
The Libyan Journal of Medicine Dec 2021Despite the high efficacy and safety of direct-acting antivirals against hepatitis C virus shown in clinical trials, treatment failures continue to occur. Our aim was... (Observational Study)
Observational Study
Despite the high efficacy and safety of direct-acting antivirals against hepatitis C virus shown in clinical trials, treatment failures continue to occur. Our aim was to establish the effectiveness of these drugs in routine clinical practice, as well as to determine factors that could influence the response to the treatment. Single-center, observational, retrospective study. Clinical, virological and pharmacotherapeutic variables were registered at baseline. Adverse drug reactions that occurred were recorded until week 24 of follow-up. Achievement of sustained virologic response was also recorded. Univariate and multivariate analysis were done to determine factors of response. A total of 333 treatment regimens corresponding to 330 different patients were evaluated. Sustained virologic response rate was 94.6% [95%CI: 91.6-96.6%]. 67.9% of the patients experienced adverse drugs reactions (92.2% were grade 1). The univariate analysis identified a higher baseline of platelets, albumin and total cholesterol as predictive factors of sustained virologic response (p < 0.05). Presence of diabetes and complications related to liver disease (splenomegaly, portal hypertension, portal hypertensive gastropathy), body mass index ≥30, greater liver fibrosis, receiving simeprevir and higher baseline levels of glucose, aspartate-aminotransferase, alanine-aminotransferase and alkaline-phosphatase, have been identified as predictive factors of non-response (p < 0.05). The multivariate analysis detected the following independent factors of non-response: body mass index ≥30 and presence of complications related to liver disease. The effectiveness and safety of direct-acting antivirals against hepatitis C virus have been maintained in routine clinical practice. Further research on predictive factors of response is required in order to develop more reliable and reproducible predictive models.
Topics: Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Pharmaceutical Preparations; Retrospective Studies; Treatment Outcome
PubMed: 34308801
DOI: 10.1080/19932820.2021.1949797 -
Antimicrobial Agents and Chemotherapy Aug 2021Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant...
Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC) of ∼40 μM. Among the macrocyclic PIs, simeprevir had the highest (EC, 15 μM) and glecaprevir the lowest (EC, >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had ECs of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC boceprevir or 1-fold EC simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Chlorocebus aethiops; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Protease Inhibitors; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vero Cells; Viral Protease Inhibitors; COVID-19 Drug Treatment
PubMed: 34097489
DOI: 10.1128/AAC.02680-20 -
ACS Central Science May 2021The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health....
The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir . Mechanistically, we showed that simeprevir not only inhibits the main protease (M) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.
PubMed: 34075346
DOI: 10.1021/acscentsci.0c01186 -
Oxford Medical Case Reports May 2021The favorable impact of antiviral therapy on low-grade hepatitis C virus (HCV)-related non-Hodgkin lymphoma manifesting as marginal zone lymphoma (MZL) has been reported...
The favorable impact of antiviral therapy on low-grade hepatitis C virus (HCV)-related non-Hodgkin lymphoma manifesting as marginal zone lymphoma (MZL) has been reported in some clinical studies. However, primary HCV-related marginal zone lymphomas (MZLs) confined to the liver have not been described in the literature nor have the resolution of liver lymphoma through anti-HCV eradication treatment. The authors report a genotype 1b HCV-positive patient with chronic hepatitis who exhibited lesions involving both hepatic lobes resembling hepatocellular carcinoma. Liver biopsy revealed an MZL of the liver. Antiviral treatment using sofosbuvir associated with simeprevir as unique treatment was started and resulted in complete haematological response. In HCV-related MZL isolated to the liver, antiviral treatment has led to the eradication of viral infection and a complete haematological response. Antiviral therapy should be considered as a first-line treatment for HCV-related primary MZLs of the liver.
PubMed: 34055359
DOI: 10.1093/omcr/omab022 -
Physical Chemistry Chemical Physics :... Jun 2021The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein...
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein binds to the human angiotensin-converting enzyme 2 (hACE2). This binding requires the RBD to undergo a conformational change from a closed to an open state. In the present study, a key pair of salt bridges formed by the side chains of K537 and E619, residues at the interfaces of SD1 and SD2, respectively, was identified to promote the opening of the RBD. Mutations of K537Q and E619D reduced their side chain lengths and eliminated this pair of salt bridges; as a result, the opening of the RBD was not observed in the MD simulations. Thus, blocking the formation of this pair of salt bridges is a promising approach for treating novel coronavirus disease 2019 (COVID-19). FDA approved drug molecules were screened by their capabilities of blocking the formation of the key pair of salt bridges, achieved by their positional stabilities in the cavity containing the side chains of K537 and E619 formed in the interface between SD1 and SD2. Simeprevir, imatinib, and naldemedine were identified to possess the desired capability with the most favorable interaction energies.
Topics: Antiviral Agents; Drug Design; Drug Evaluation, Preclinical; Humans; Imatinib Mesylate; Molecular Docking Simulation; Naltrexone; Protein Domains; SARS-CoV-2; Simeprevir; Spike Glycoprotein, Coronavirus
PubMed: 34008647
DOI: 10.1039/d1cp01045j -
Cell Reports May 2021Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2...
Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (M) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the M substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 M protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their M inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PL). HCV drugs that inhibit PL synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit M do not synergize with remdesivir.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Cell Culture Techniques; Cell Line; Coronavirus Papain-Like Proteases; Drug Repositioning; Drug Synergism; Hepacivirus; Hepatitis C; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protease Inhibitors; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment
PubMed: 33984267
DOI: 10.1016/j.celrep.2021.109133 -
Journal of Biomolecular Structure &... 2022In March 2020, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2...
In March 2020, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Since then, the search for a vaccine or drug for COVID-19 treatment has started worldwide. In this regard, a fast approach is the repurposing of drugs, primarily antiviral drugs. Herein, we performed a virtual screening using 22 antiviral drugs retrieved from the DrugBank repository, azithromycin (antibiotic), ivermectin (antinematode), and seven non-structural proteins (Nsps) of SARS-CoV-2, which are considered important targets for drugs, via molecular docking and molecular dynamics simulations. Drug-receptor binding energy was employed as the main descriptor. Based on the results, paritaprevir was predicted as a promising multi-target drug that favorably bound to all tested Nsps, mainly adipose differentiation-related protein (ADRP) (-36.2 kcal mol) and coronavirus main proteinase (Mpro) (-32.2 kcal mol). Moreover, the results suggest that simeprevir is a strong inhibitor of Mpro (-37.2 kcal mol), which is an interesting finding because Mpro plays an important role in viral replication. In addition to drug-receptor affinity, hot spot residues were characterized to facilitate the design of new drug derivatives with improved biological responses.
Topics: Humans; SARS-CoV-2; Antiviral Agents; Molecular Docking Simulation; COVID-19; COVID-19 Drug Treatment; Drug Repositioning; Protease Inhibitors; Viral Nonstructural Proteins; Molecular Dynamics Simulation
PubMed: 33949279
DOI: 10.1080/07391102.2021.1921033 -
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 -
Drug Development Research Dec 2021Leishmaniasis is a vector-borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral...
Leishmaniasis is a vector-borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C-24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)-approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC ) of 51.49 ± 5.87 μM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125-μM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach.
Topics: Drug Approval; Drug Repositioning; Leishmania donovani; Leishmaniasis, Visceral; Methyltransferases; Simeprevir
PubMed: 33929761
DOI: 10.1002/ddr.21820