scholarly journals Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4813
Author(s):  
Marcella Bassetto ◽  
Cecilia M. Cima ◽  
Mattia Basso ◽  
Martina Salerno ◽  
Frank Schwarze ◽  
...  
Keyword(s):  
Zika Virus ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Health Concern ◽  
Virus Infections ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Further Development

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

scholarly journals Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 223 ◽  
Author(s):  
Sara Sobhy Kishta ◽  
Reem El-Shenawy ◽  
Sobhy Ahmed Kishta
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

scholarly journals Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 223
Author(s):  
Sara Sobhy Kishta ◽  
Sobhy Ahmed Kishta ◽  
Reem El-Shenawy
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection

Gut ◽  
2017 ◽  
Vol 67 (7) ◽  
pp. 1342-1350 ◽  
Author(s):  
Hung-Yu Sun ◽  
Pin-Nan Cheng ◽  
Chiung-Ying Tseng ◽  
Wei-Jen Tsai ◽  
Yen-Cheng Chiu ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Sustained Virological Response Rate ◽  
Antiviral Agents ◽  
Density Lipoprotein ◽  
Antiviral Agent ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Direct Acting

ObjectiveLipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment.DesignTwenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unitResultsDAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism.ConclusionThe DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.

scholarly journals In VitroActivity and Resistance Profile of Samatasvir, a Novel NS5A Replication Inhibitor of Hepatitis C Virus

2014 ◽  
Vol 58 (8) ◽  
pp. 4431-4442 ◽  
Author(s):  
J. P. Bilello ◽  
L. B. Lallos ◽  
J. F. McCarville ◽  
M. La Colla ◽  
I. Serra ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Genotype 1A ◽  
Hcv Protease ◽  
Chronic Hcv ◽  
Direct Acting

ABSTRACTThe hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated thein vitroactivity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 μM provided a selectivity index of >5 × 107. Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replicationin vitroand is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.

scholarly journals Impact of Preexisting Hepatitis C Virus Genotype 6 NS3, NS5A, and NS5B Polymorphisms on theIn VitroPotency of Direct-Acting Antiviral Agents

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Fiona McPhee ◽  
Joseph Ueland ◽  
Vincent Vellucci ◽  
Scott Bowden ◽  
William Sievert ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Virologic Response ◽  
Virus Genotype ◽  
Direct Acting Antiviral ◽  
East And Southeast Asia ◽  
Direct Acting ◽  
Ns3 Protease

ABSTRACTHCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAAin vitropotency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (<4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S).In vitrosusceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC90] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC90range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC90[L28A-R30S] of ≥720 nM or EC90[L28T-R30S] of ≥128 nM against tested DAAs) or as L28T-L31I (EC90[tested DAAs] of >5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

scholarly journals Viekira Pak Induced Fatal Lactic Acidosis: A Case Report of an Unusual Side Effect

2016 ◽  
Vol 2016 ◽  
pp. 1-3 ◽  
Author(s):  
Molham Abdulsamad ◽  
Ariyo Ihimoyan
Keyword(s):  
Lactic Acidosis ◽  
Side Effect ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Direct Acting Antiviral ◽  
First Case ◽  
Safety Warning ◽  
Chronic Hcv ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Viekira Pak is a new direct-acting antiviral agent that has an excellent efficacy in treating patients with chronic HCV. FDA released a safety warning that Viekira Pak can cause serious liver injury mostly in patients with underlying advanced liver disease. We report the first case of fatal lactic acidosis presenting 3 days after initiating therapy with Viekira Pak. Although it is very hard to precisely determine the cause of lactic acidosis, our case highlights an unusual side effect that ensued after starting the medication. Given the complexity of drug-drug interactions that can happen with the new direct-acting antiviral agents and the paucity of data regarding coadministration and methods of monitoring, a thorough review should be pursued prior to initiating these medications.

scholarly journals Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 790
Author(s):  
Dong Lin ◽  
Venu Reddy ◽  
Hanadi Osman ◽  
Adriana Lopez ◽  
Ali Riza Koksal ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Hcv Infection ◽  
Novel Therapy ◽  
Direct Acting Antiviral ◽  
Chronic Hcv Infection ◽  
Gsk 3Β ◽  
Chronic Hcv ◽  
Signaling Activation ◽  
Direct Acting

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.

scholarly journals Baseline thrombopoietin level is associated with platelet count improvement in thrombocytopenic chronic hepatitis C patients after successful direct-acting antiviral agent therapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yen-Chun Chen ◽  
Ping-Hung Ko ◽  
Chi-Che Lee ◽  
Chih-Wei Tseng ◽  
Kuo-Chih Tseng
Keyword(s):  
Chronic Hepatitis ◽  
Platelet Count ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Characteristic Curve ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Improvement Ratio

Abstract Background Thrombocytopenia can rapidly improve in chronic hepatitis C (CHC) patients receiving direct-acting antiviral agents (DAA). The role of baseline (BL) thrombopoietin (TPO) in this phenomenon is unclear. Methods From June 2016 to February 2019, a total of 104 CHC patients receiving DAA, with a sustained virologic response and BL thrombocytopenia, at Dalin Tzu Chi Hospital, were enrolled in this retrospective study. Significant platelet count improvement and platelet count improvement ratio were analyzed for correlation with BL TPO. Results This cohort included 40 men (38.5%). Seventy-two (69.2%) patients had advanced fibrosis. The platelet count [median (range)] increased from 110.5 (32–149) × 103/µL at BL to 116.5 (40–196) and 118.0 (35–275) × 103/µL at end of treatment (EOT) and 12 weeks after EOT (P12), respectively, (EOT vs. BL, P < 0.001; P12 vs. BL, P < 0.001). BL TPO was positively correlated with significant platelet count improvement (P < 0.001), platelet count improvement ratio at EOT (P = 0.004), and P12 (P < 0.001). The area under the receiver operating characteristic curve and optimal cutoffs (pg/ml) were 0.77 (95% confidence interval, 0.67–0.86) and 120, respectively, for significant platelet count improvement prediction. The sensitivity, specificity, and accuracy were 88.6%, 71.7%, and 78.8%, respectively. Conclusions BL TPO level might be a useful marker for predicting significant platelet count improvement in thrombocytopenic patients after successful DAA therapy.

scholarly journals Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 223 ◽  
Author(s):  
Sara Sobhy Kishta ◽  
Reem El-Shenawy ◽  
Sobhy Ahmed Kishta
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system and human hepatocyte-like cells from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

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