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1.
Medicine (Baltimore) ; 99(11): e19140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176039

RESUMO

Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107 HIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680 cells/mm, HIV viral load (VL) was <40 copies/mL in 94% and median HCV VL was 2,257,403 IU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Coinfecção/tratamento farmacológico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/complicações , Uridina Monofosfato/análogos & derivados , Afro-Americanos/estatística & dados numéricos , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Estudos Retrospectivos , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico
2.
Expert Opin Drug Metab Toxicol ; 16(2): 97-101, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32003256

RESUMO

Introduction: Despite the high rate of response, the treatment of special populations, the management of patients with previous failure to direct-acting antiviral (DAA) regimens, and the development of drug resistance are still a challenge. Moreover, the FDA suggested stopping research on new DAA because of the high efficacy of those already available.Areas covered: Understanding pharmacokinetic/pharmacodynamic parameters could be a simple and effective way to improve the management of anti-hepatitis C virus (HCV) treatment. The aim of this review is to provide an overview of this aspect in order to offer a new insight into treatment choice.Expert opinion: Clinicians should offer an adequate strategy for HCV treatment taking into consideration patient-related factors and by improving their knowledge of the antiviral activity and pharmaceutical 'forgiveness' of each DAA.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Antivirais/farmacocinética , Farmacorresistência Viral , Hepatite C/virologia , Humanos
3.
Expert Opin Pharmacother ; 21(3): 261-273, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31914336

RESUMO

Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.


Assuntos
Benzazepinas/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Indóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Antivirais/uso terapêutico , Combinação de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/prevenção & controle , Resposta Viral Sustentada , Comprimidos , Resultado do Tratamento
4.
Chem Commun (Camb) ; 55(93): 14027-14030, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690898

RESUMO

RNA-biased small molecules with a monoquinoxaline core target the L-shaped structure of subdomain IIa of Hepatitis C virus internal ribosome entry site (IRES) RNA in proximity to the Mg2+ binding site. The binding event leads to the destacking of RNA bases, resulting in the inhibition of IRES-mediated translation and HCV RNA replication.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Sítios Internos de Entrada Ribossomal/efeitos dos fármacos , Quinoxalinas/farmacologia , RNA Viral/efeitos dos fármacos , Antivirais/química , Hepacivirus/genética , Humanos , Sítios Internos de Entrada Ribossomal/genética , Conformação Molecular , Quinoxalinas/química , RNA Viral/genética , Replicação Viral/efeitos dos fármacos
5.
Orv Hetil ; 160(40): 1591-1602, 2019 Oct.
Artigo em Húngaro | MEDLINE | ID: mdl-31565976

RESUMO

Introduction: Liver cirrhosis (20-25%), hepatocellular carcinoma (1.5-3%), insulin resistance (30-40%) and type 2 diabetes (25-30%) are common complications in patients with chronic hepatitis C virus (HCV) infection; however, data are missing from Hungary. Aim: To determine the prevalence of diabetes and insulin resistance in Hungarian HCV patients; to evaluate treatment-induced metabolic changes in relation to diabetes/insulin resistance and virological response and to perform a sustained follow-up for hepatocellular carcinoma detection. Method: We enrolled 150 Hungarian HCV genotype 1 patients (mean age: 48.55 ± 8.55 years, male/female ratio: 45/55%) from 2007-2012. We analysed their baseline, week 12, and end of therapeutic follow-up (24 weeks after interferon-based therapy completion) laboratory data. We performed a 5-year follow-up (2012-2017). Results: The prevalence of insulin sensitivity, insulin resistance and diabetes was 37.4%, 35.3% and 27.3%, respectively. Insulin resistant and diabetic patients showed a decrease in fasting glucose from baseline to end of follow-up (5.47 ± 0.66 vs. 5.08 ± 0.60, p<0.001; 7.90 ± 2.67 vs. 7.04 ± 2.75, p = 0.006), as did both the sustained responder and non-responder groups. Treatment efficacy rate was poor in diabetic vs. insulin sensitive and insulin resistant groups (17% vs. 46% and 40%); insulin sensitivity was not a predictor of virological response. Three participants with diabetes were diagnosed with hepatocellular carcinoma during follow-up by regular ultrasound examinations. Conclusion: Hungarian HCV patients showed high prevalence of diabetes and insulin resistance, though antiviral therapy caused favourable changes in their carbohydrate metabolism. Antiviral therapy was less effective in diabetic patients. Follow-up ultrasound examinations are required for hepatocellular carcinoma in HCV patients, especially those with diabetes. Orv Hetil. 2019; 160(40): 1591-1602.


Assuntos
Antivirais/uso terapêutico , Glicemia/metabolismo , Carcinoma Hepatocelular/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/terapia , Resistência à Insulina , Neoplasias Hepáticas/complicações , Adulto , Idoso , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Hungria/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência
6.
BMC Infect Dis ; 19(1): 875, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640596

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana. METHODS: This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis. RESULTS: Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations - K10Q and R70Q - were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments. CONCLUSION: Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.


Assuntos
Hepacivirus/genética , Hepatite C/virologia , Mutação , Filogenia , Adulto , Antivirais/uso terapêutico , Botsuana , Carcinoma Hepatocelular/virologia , Estudos Transversais , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Ribavirina/uso terapêutico
7.
Eur J Med Chem ; 184: 111747, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604164

RESUMO

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4-6(a-f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13-15(a-f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 µM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 µM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 µM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 µM) relative to VCH-759 (EC50 = 5.29 µM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 µM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 µM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hepacivirus/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/farmacologia , Triazinas/síntese química , Triazinas/química , Triazinas/farmacologia , Proteínas não Estruturais Virais/metabolismo
8.
Life Sci ; 238: 116958, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628915

RESUMO

AIM: To work on Hepatitis C Virus (HCV), one of the major causes of liver cirrhosis and hepatocellular carcinoma, polymerase of genotype 4a that have no solved structures deposited in the protein data bank (PDB) yet. Understanding the dynamics and testing some novel inhibitors are also covered. MATERIALS AND METHODS: Molecular Dynamics Simulation (MDS) is performed for a period of 1 µs on comparatively modeled then validated NS5b of subtype 4a. Following MDS analysis, molecular docking is performed to test the inhibitory performance of eight novels suggested guanosine derivatives using 181 different conformations of the protein model gathered during the MDS run after the equilibration period. KEY FINDINGS: The results yield that the eight modified, at position 2', GTP derivatives (fluorine, Hydroxyl, and sulphonyl oxydanyl) have binding energies comparable to the parent molecule, GTP. Besides, the eight suggested compounds have lower binding energies (and hence better in binding) compared to sofosbuvir (a drug approved by FDA in 2013 against HCV) and ribavirin (a wide range acting antiviral drug used before against HCV). SIGNIFICANCE: Combined molecular dynamics and molecular docking are able to test the hypothesis of HCV polymerase dynamics doesn't affect the nucleotides (or nucleotide inhibitors) binding to its active site. Despite the reported highly dynamic subtype 4a of HCV; all the nucleotide inhibitors under the study are able to, tightly, bind to NS5b of genotype 4a. This behavior is reported before for the Zika virus polymerase, as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Guanosina Trifosfato/química , Hepacivirus/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas não Estruturais Virais/antagonistas & inibidores , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Modelos Moleculares , Conformação Proteica , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
9.
Chem Biodivers ; 16(11): e1900315, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31532059

RESUMO

Here, we report the synthesis and characterization of four new aroyl-hydrazone derivatives L1 -L4 , and their structural as well as biological activities have been explored. In addition to docking with bovine serum albumin (BSA) and duplex DNA, the experimental results demonstrate the effective binding of L1 -L4 with BSA protein and calf thymus DNA (ct-DNA) which is in agreement with the docking results. Further biological activities of L1 -L4 have been examined through molecular docking with different proteins which are involved in the propagation of viral or cancer diseases. L1 shows best binding affinity with influenza A virus polymerase PB2 subunit (2VY7) with binding energy -11.42 kcal/mol and inhibition constant 4.23 nm, whereas L2 strongly bind with the hepatitis C virus NS5B polymerase (2WCX) with binding energy -10.47 kcal/mol and inhibition constant 21.06 nm. Ligand L3 binds strongly with TGF-beta receptor 1 (3FAA) and L4 with cancer-related EphA2 protein kinases (1MQB) with binding energy -10.61 kcal/mol, -10.02 kcal/mol and inhibition constant 16.67 nm and 45.41 nm, respectively. The binding energies of L1 -L4 are comparable with binding energies of their proven inhibitors. L1 , L3 and L4 can be considered as both 3FAA and 1MQB dual targeting anticancer agents, while L1 and L3 are both 2VY7 and 2WCX dual targeting antiviral agents. On the other side, L2 and L4 target only one virus related target (2WCX). Furthermore, the geometry optimizations of L1 -L4 were performed via density functional theory (DFT). Moreover, all four ligands (L1 -L4 ) were characterized by NMR, FT-IR, ESI-MS, elemental analysis and their molecular structures were validated by single crystal X-ray diffraction studies.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , DNA/antagonistas & inibidores , Desenho de Drogas , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Soroalbumina Bovina/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , DNA/química , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Hepacivirus/efeitos dos fármacos , Hidrazonas/síntese química , Hidrazonas/química , Vírus da Influenza A/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Soroalbumina Bovina/química
10.
Int J Mol Sci ; 20(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561440

RESUMO

Claudins regulate paracellular permeability in different tissues. The claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) is a known modulator of a claudin subset. However, it does not efficiently bind to claudin-1 (Cldn1). Cldn1 is a pharmacological target since it is (i) an essential co-receptor for hepatitis C virus (HCV) infections and (ii) a key element of the epidermal barrier limiting drug delivery. In this study, we investigated the potential of a Cldn1-binding cCPE mutant (i) to inhibit HCV entry into hepatocytes and (ii) to open the epidermal barrier. Inhibition of HCV infection by blocking of Cldn1 with cCPE variants was analyzed in the Huh7.5 hepatoma cell line. A model of reconstructed human epidermis was used to investigate modulation of the epidermal barrier by cCPE variants. In contrast to cCPEwt, the Cldn1-binding cCPE-S305P/S307R/S313H inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner. In addition, TJ modulation by cCPE variant-mediated targeting of Cldn1 and Cldn4 opened the epidermal barrier in reconstructed human epidermis. cCPE variants are potent claudin modulators. They can be applied for mechanistic in vitro studies and might also be used as biologics for therapeutic claudin targeting including HCV treatment (host-targeting antivirals) and improvement of drug delivery.


Assuntos
Claudinas/metabolismo , Enterotoxinas/metabolismo , Hepatócitos/metabolismo , Pele/metabolismo , Substituição de Aminoácidos , Linhagem Celular Tumoral , Claudinas/química , Enterotoxinas/química , Enterotoxinas/farmacologia , Epiderme/metabolismo , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Pele/citologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral
11.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540136

RESUMO

Insulin resistance and diabetes are both associated with chronic hepatitis C virus (HCV) infection, and the glucagon-like peptide-1(GLP-1) receptor agonist, liraglutide, is a common therapy for diabetes. Our aim was to investigate whether liraglutide treatment can inhibit HCV replication. A cell culture-produced HCV infectious system was generated by transfection of in vitro-transcribed genomic JFH-1 ribonucleic acid (RNA) into Huh-7.5 cells. Total RNA samples were extracted to determine the efficiency of HCV replication. The Ava5 cells were treated with liraglutide and cell viability was calculated. A Western blot analysis of the protein expression was performed. The immunoreactive blot signals were also detected. Liraglutide activated GLP-1 receptors in the HCV infectious system, and inhibited subgenomic HCV RNA replication in the HuH-7.5 cells. The Western blot analysis revealed both HCV protein and replicon RNA were reduced after treatment with liraglutide in a dose-dependent manner. Liraglutide decreased the cell viability of HCV RNA at an optimum concentration of 120 µg/mL, activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and the phosphorylated- transducer of regulated cyclic adenosine monophosphate (CAMP) response element-binding protein 2 (TORC2), thereby decreasing the cell viability of phosphoenolpyruvate carboxykinase (PEPCK) and G6pase RNA Therefore, we conclude that liraglutide can inhibit HCV replication via an AMPK/TORC2-dependent pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hepacivirus/efeitos dos fármacos , Hepatócitos/enzimologia , Liraglutida/farmacologia , Replicação Viral/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hepacivirus/fisiologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Eur J Med Chem ; 183: 111723, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557613

RESUMO

A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.


Assuntos
Antivirais/química , Antivirais/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Isomerismo , Replicação Viral/efeitos dos fármacos
13.
Nat Commun ; 10(1): 3468, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371704

RESUMO

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antivirais/química , Linhagem Celular Tumoral , Desenho de Drogas , Farmacorresistência Viral/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C/virologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Estudo de Prova de Conceito , Inibidores de Proteases/química , Proteólise/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Proteínas não Estruturais Virais/metabolismo
14.
Acta Med Indones ; 51(2): 128-136, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31383827

RESUMO

BACKGROUND: HIV infection in HCV-infected patients accelerates disease progression and reduces the success rate of Peg-IFN/RBV treatment. HCV mutation in NS5A-ISDR/PKR-BD region improved the outcome in HCV monoinfection treated with Peg-IFN/RBV. SNP-IL28B polymorphism is predicted to have an effect on HCV quasispecies evolution. However, the role of NS5A mutation and SNP IL-28B in HIV-HCV coinfection is still unclear. The aim of the study is to determine the role of HCV NS5A-ISDR/PKR-BD mutation and SNP IL-28 polymorphism on the successfulness of Peg-IFN/RBV therapy in HCV-HIV coinfection. METHODS: prospective cohort was performed in this study. Plasma sample were obtained from 30 and 8 patients with HCV-HIV coinfection and HCV monoinfection, respectively. PCR nucleotide sequencing was performed after RNA virus extraction and cDNA synthesis. Protein secondary structure and prediction of mutation function were analyzed using PredictProtein (PP) program. RESULTS: sixteen HCV-HIV coinfected patients and none from eight HCV patients achieved sustained virological response (SVR). ≥1 non-neutral mutation was found in 24/30 HCV-HIV coinfection and more frequent in SVR group (14 patients). ≥1 non-neutral mutation were found statistically significant for overall SVR achievement (p<0.05) in all patients regardless of coinfection or monoinfection status. Of the 27 HCV-HIV coinfected patients with CC-gene, 21 subjects had non-neutral mutation. The structure which was expected as NS5A binding site structure was different from consensus (wild type) in SVR group, while the structure was similar to consensus in non-SVR group. CONCLUSION: having ≥1 non-neutral mutation was associated with SVR achievement in Peg-IFN/RBV therapy, regardless of monoinfection and coinfection status.


Assuntos
Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Interferons/genética , Proteínas não Estruturais Virais/genética , Adulto , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Polietilenoglicóis , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Ribavirina/uso terapêutico , Resposta Viral Sustentada
15.
PLoS Pathog ; 15(8): e1007949, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31374104

RESUMO

Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Infecções por Flavivirus/imunologia , Flavivirus/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Imunidade Inata/imunologia , Proteínas com Domínio LIM/fisiologia , Fator de Transcrição STAT2/metabolismo , Animais , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Infecções por Flavivirus/tratamento farmacológico , Infecções por Flavivirus/virologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon-alfa/farmacologia , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , NF-kappa B , Fator de Transcrição STAT2/genética , Transdução de Sinais
16.
World J Gastroenterol ; 25(29): 3929-3940, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31413528

RESUMO

Hepatocellular carcinoma (HCC) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis C virus (HCV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HCV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of HCC, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for HCC occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization's goals for eradication of HCV are being endorsed worldwide, the elimination of HCV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HCV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and HCC in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop HCC even in the absence of cirrhosis. Furthermore, HCC treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of HCC suggest the beginning of a new era: The post-HCV era. Changes may eventually undermine current practices of early detection, surveillance and management of HCC. We focused on the risk of HCC occurrence and recurrence in the post-HCV era, the surveillance needed after DAA therapy and current studies in HCC patients with NAFLD.


Assuntos
Antivirais/efeitos adversos , Carcinoma Hepatocelular/etiologia , Detecção Precoce de Câncer/métodos , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Progressão da Doença , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Transplante de Fígado/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Resposta Viral Sustentada
17.
Protein Pept Lett ; 26(12): 930-939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31441722

RESUMO

BACKGROUND: Supercharged GFP proteins were known as effective carriers for delivery of macromolecules into eukaryotic cells as well as fluorescent fusion tags for in vitro and in vivo detection. OBJECTIVE: Herein, anti-viral effects of +36 GFP and its anti-tumor effects were studied in vitro and in vivo, respectively. METHODS: We evaluated anti-HIV, anti-HSV, and anti-HCV effects of +36 GFP in vitro using ELISA, and real time PCR as common techniques for their detection, respectively. Moreover, we assessed the role of +36 GFP for eliciting HPV-related anti-tumor effects in mice due to the lack of HPV replication in vitro. RESULTS: Our data showed that +36 GFP efficiently enter the cells and augment the transfection rate of HPV16E7 antigen, as well. Furthermore, +36 GFP significantly reduced HCV, HIV and HSV replication up to 75%, 49% and 43% in HCV-infected Huh7.5 cells, HIV-infected Hela cells and HSV-infected Vero cells, respectively. On the other hand, mice immunization with +36 GFP complexed with HPV16 E7 antigen (+36GFP + E7) or fused to HPV16 E7 antigen (+36GFP-E7) elicited a higher Th1 cellular immune response with the predominant IgG2a, IgG2b, IFN-γ and Granzyme B levels than those induced by other groups. These regimens protected mice against TC- 1 tumor challenge (~ 67%) compared to E7 protein alone (~ 33%). These data suggested that +36 GFP can act as an anti-viral agent at certain dose due to its high efficiency in cell penetration in vitro and in vivo. CONCLUSION: Generally, +36 GFP targets viral replication in vitro as well as helps to suppress the growth of HPV-related tumors in vivo.


Assuntos
Antivirais/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas Mutantes/genética , Vacinas contra Papillomavirus/genética , Proteínas Recombinantes de Fusão/genética , Animais , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Linhagem Celular , Feminino , Granzimas/metabolismo , Proteínas de Fluorescência Verde/imunologia , HIV/efeitos dos fármacos , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Hepacivirus/efeitos dos fármacos , Papillomavirus Humano 16/efeitos dos fármacos , Humanos , Imunidade Celular , Interferon gama/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Mutantes/imunologia , Proteínas Mutantes/farmacologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Replicação Viral/efeitos dos fármacos
18.
Diabetes Metab Syndr ; 13(4): 2641-2646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405688

RESUMO

BACKGROUND AND OBJECTIVES: sustained virologic response (SVR) can be achieved in high percentage of HCV patients with the availability of direct acting antiviral agents DAAs. However, the effect of DAAs on insulin resistance and T2DM has yet to be clearly documented in spite of higher prevalence of T2DM in chronic HCV patients. This study tested the hypothesis that eradication of HCV is associated with either complete recovery or improvement of the symptoms of IR and T2DM. PATIENTS AND METHODS: In our study 240 Chronic HCV patients candidate to centers of NCCVH with Coordination to departments of internal medicine and clinical pathology, Zagzig University for treatment with DAAs. Measurement of HbA1c, FPG and fasting insulin hormone and calculation of HOMA-IR before and 3 months after DDAs therapy is done. Statistical analysis was done for these data. RESULTS: After SVR; HbA1c decreased from 7.6 ±â€¯0.69 to 6.7 ±â€¯0.78 in diabetic group and from 5.8 ±â€¯0.5 to 5.1 ±â€¯0.3 in non-diabetic group, with decreased in the percentage of uncontrolled T2DM patients from 22.4% to 5.2% after treatment. HOMA-IR decreased in diabetic group from 4.9 ±â€¯0.7 to 3.7 ±â€¯0.75 and in non-diabetic group from 3.1 ±â€¯0.56 to 2.3 ±â€¯0.4 with complete improvement of IR to ≤2.5 in 20.7% of diabetic patients. 20% of diabetic patient needed to decrease oral hypoglycemic dose and 13.3% of them needed to decrease insulin dose. CONCLUSIONS: This study shows that eradication of HCV by DAAs will result in a parallel decrease in IR and improve clinical outcomes in patients with established T2DM.


Assuntos
Antivirais/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Resistência à Insulina , Adolescente , Adulto , Idoso , Biomarcadores/análise , Glicemia/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/virologia , Egito/epidemiologia , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
19.
Asian Pac J Cancer Prev ; 20(8): 2311-2317, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450900

RESUMO

Background: Even with the fantastic successes of direct-acting antivirals (DAA) in the treatment of Hepatitis C Virus (HCV) infection, natural drug resistance remains a challenging obstacle for their impacts. The data regarding protease inhibitors (PIs) resistance in Iran population are limited. The aim of this study was to investigate the variations in NS3 protease of HCV from non-responder patients. Methods: In this cross-sectional study, 14 HCV infected patients with genotype 1(N=5) and 3(N=9) who have not responded to Interferon-related regime were enrolled from Liver Clinic, Shiraz. The NS3 protease region was amplified by Nested-PCR followed by product gel extraction. Besides, some amplified protease regions were cloned into a cloning vector to improve the sensitivity of mutation detection. Both crude and cloned sequences were then introduced into sequencing. The obtained sequences were compared with the NS3 reference sequences and analyzed by Geno2pheno available software to find possible substitutions. In the end, the phylogenetic tree was constructed. Results: Among variations responsible for PIs resistance, only one out of 14 (7%) sample who was infected with genotype 1a, harbored R117C+N174S double mutation, which causes reduced susceptibility to Telaprevir. Any another resistance mutation was not found among the studied population. The most frequent substitutions were determined as I52M(N=9), S102A(N=9), S166A(8) and V170I(8) for genotype 3a, and F147S/A(4) for genotype 1. However, some uncharacterized substitutions on scored position, including I132L(N=1), I170V(N=3) and N174S(N=2) were also determined among sequences. Phylogenetic analysis demonstrated that the protease region has enough power to correctly classify enrolled samples into relevant clusters on the tree. There were 2, 3 and 9 cases of sub-genotypes 1a, 1b, and 3a, respectively. Conclusion: A low frequency of PIs resistance mutations in our HCV infected population is a hopeful point of starting these drugs in HCV infected patients.


Assuntos
Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Mutação , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Adulto , Idoso , Substituição de Aminoácidos , Antivirais/farmacologia , Estudos Transversais , Feminino , Seguimentos , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia
20.
J Formos Med Assoc ; 118(8): 1187-1192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279502

RESUMO

BACKGROUND: Glecaprevir/pibrentasvir (GLE/PIB) is a pangenotypic direct-acting antiviral agent for the treatment of chronic hepatitis C virus (HCV) infection. Real-world data of GLE/PIB in Asian patients other than Japanese are limited. We thus investigated the effectiveness and safety profile of GLE/PIB in Taiwanese patients with chronic hepatitis C (CHC). METHODS: CHC patients who received 8, 12, or 16 weeks of GLE/PIB between August and October of 2018 were consecutively enrolled. The treatment duration was determined according to drug label. The hepatic fibrosis was staged according to liver histology, transient elastography, fibrosis index based on 4 factors (FIB-4), or findings of ultrasonography/endoscopy. The primary endpoint was sustained virological response at week 12 off therapy (SVR12). The safety profiles were also assessed. RESULTS: A total of 110 CHC patients with 51% of males were enrolled. The median age was 70 years. A majority (82%) of patients were infected with HCV genotype 2. Forty-six (42%) and 64 (58%) patients had advanced hepatic fibrosis and compensated cirrhosis, respectively. Forty-five (41%) non-cirrhotic patients were treated for 8 weeks. The overall SVR12 rates were 100%, regardless of baseline clinical characteristics. The common adverse events (AEs) were pruritus (12%), anorexia (6%), and fatigue (5%). Nine (8%) serious AEs unrelated to GLE/PIB occurred. Three (2%) patients had Grade 3 elevation of total bilirubin level. None had premature treatment termination, hepatic decompensation, or death. CONCLUSION: Interferon-free GLE/PIB regimen is highly effective and safe for Asian chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Estudos Retrospectivos , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Taiwan
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