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1.
Acta Virol ; 63(3): 261-269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507191

RESUMO

Bovine viral diarrhea virus (BVDV) exists in two main biotypes: cytopathic (cp) and noncytopathic (ncp). Although some studies were done on the effect of interferon alpha (IFN-α) on BVDV, the effect of exogenous IFN against BVDV biotypes remains unclear. In the present study, we evaluated the comparative effect of exogenous human IFN-α (HuIFN-α) on different BVDV biotypes and genotypes. The results showed that exogenous HuIFN-α greatly inhibited the growth of different BVDV biotypes and genotypes. However, HuINF-α has a significant inhibitory effect on cp biotype compared to ncp one without significant variation between different genotypes. The effect of HuIFN-α on BVDV reached the maximum level at early stages of infection (0-20 h post infection) and increased in a dose-dependent manner (10-500 U/ml). Quantitative real-time RT-PCR was used to evaluate the effect of exogenous HuIFN-α on RNA synthesis of both BVDV biotypes. HuIFN-α reduced RNA production of cp by 4 logs compared to only 2 logs for ncp strains. Additionally, the antiviral effect of IFN-α against both BVDV biotypes seems to be independent of the RNA-dependent protein kinase (PKR) activation as assayed by direct analysis of in vivo phosphorylation of eIF2-α and by 2-aminopurine (2-AP) treatment. Collectively, these results indicated that the exogenous HuIFN-α treatment has an inhibitory effect not only on cp BVDV biotype but also on the ncp BVDV. The antiviral effect of exogenous HuIFN-α was biotype, time, dose but not genotype dependent. PKR has no role in the inhibitory effect suggesting that other IFN-antiviral pathways were involved. Keywords: BVDV biotypes; HuIFN-α; RNA synthesis; PKR-independent.


Assuntos
Doença das Mucosas por Vírus da Diarreia Viral Bovina , Vírus da Diarreia Viral Bovina , Interferon-alfa , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Doença das Mucosas por Vírus da Diarreia Viral Bovina/tratamento farmacológico , Doença das Mucosas por Vírus da Diarreia Viral Bovina/virologia , Bovinos , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Replicação Viral/efeitos dos fármacos
2.
Acta Virol ; 63(3): 278-285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507193

RESUMO

Dengue virus (DENV) infection is one of the most widely-spread flavivirus infections with no effective antiviral drugs available. Peptide inhibitors have been considered as one of the best drug candidates due to their high specificity, selectivity in their interactions and minimum side effects. In this study, we employed computational studies using YASARA, HADDOCK server and PyMOL software to generate short and linear peptides based on a reference peptide, CP5-46A, to block DENV NS2B-NS3 protease. The inhibition potencies of the peptides were evaluated using in-house DENV2 serine protease and fluorogenic peptide substrates. In vitro analyses were performed to determine the peptides cytotoxicity and the inhibitory effects against DENV2 replication in WRL-68 cells. Our computational analyses revealed that the docking energy of AYA3, a 16 amino acid (aa) (-81.2 ± 10.6 kcal/mol) and AYA9, a 15 aa peptide (-83.8 ± 6.8 kcal/mol) to DENV NS2B-NS3 protease were much lower than the reference peptide (46 aa; -70.9 ± 7.8 kcal/mol) and the standard protease inhibitor, aprotinin (58 aa; -48.2 ± 10.6 kcal/mol). Both peptides showed significant inhibition against DENV2 NS2B-NS3 protease activity with IC50 values of 24 µM and 23 µM, respectively. AYA3 and AYA9 peptides also demonstrated approximately 68% and 83% of viral plaque reduction without significantly affecting cell viability at 50 µM concentration. In short, we generated short linear peptides with lower cytotoxic effect and substantial antiviral activities against DENV2. Further studies are required to investigate the inhibitory effects of these peptides in vivo. Keywords: peptide inhibitors; dengue virus; NS2B-NS3 protease; plaque reduction.


Assuntos
Antivirais , Vírus da Dengue , Peptídeos , Inibidores de Proteases , Replicação Viral , Antivirais/farmacologia , Biologia Computacional , Vírus da Dengue/enzimologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Peptídeos/síntese química , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Replicação Viral/efeitos dos fármacos
3.
J Agric Food Chem ; 67(33): 9241-9253, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31369258

RESUMO

Antiviral compounds targeting viral replicative processes have been studied as an alternative for the control of begomoviruses. Previously, we have reported that the peptide AmPep1 has strong affinity binding to the replication origin sequence of tomato yellow leaf curl virus (TYLCV). In this study, we describe the mechanism of action of this peptide as a novel alternative for control of plant-infecting DNA viruses. When AmPep1 was applied exogenously to tomato and Nicotiana benthamiana plants infected with TYLCV, a decrease in the synthesis of the two viral DNA strands (CS and VS) was observed, with a consequent delay in the development of disease progress in treated plants. The chemical mechanism of action of AmPep1 was deduced using Raman spectroscopy and molecular modeling showing the formation of chemical interactions such as H bonds and electrostatic interactions and the formation of π-π interactions between both biomolecules contributing to tampering with the viral replication.


Assuntos
Amaranthus/química , Antivirais/química , Antivirais/farmacologia , Begomovirus/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , RNA Viral/química , Replicação Viral/efeitos dos fármacos , Begomovirus/química , Begomovirus/genética , Begomovirus/fisiologia , Sequências Repetidas Invertidas/efeitos dos fármacos , Lycopersicon esculentum/virologia , Doenças das Plantas/virologia , Proteínas de Plantas/química , RNA Viral/genética , Tabaco/virologia
4.
Arch Virol ; 164(11): 2691-2698, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31428916

RESUMO

Aleutian mink disease virus is one of the greatest threats to modern mink farming. The disease reduces fecundity and causes high mortality among kits. The aim of this study was to evaluate the effectiveness of methisoprinol in counteracting the effects of Aleutian disease, both by inhibiting replication of the virus and by mitigating the harmful effects of the disease on the fecundity and weight of infected animals. The study included 300 individuals with confirmed infection, divided according to antibody titres into three experimental groups, which received a 20% methisoprinol solution, and three control groups, which did not receive the immunostimulant. In the mink from the experimental groups, the number of copies of the genetic material of the virus in the spleens and lymph nodes was one order of magnitude lower than in the case of the control groups. Mink receiving the supplement also showed higher fecundity (on average 5.83 in the experimental groups and 4.83 in the control groups), and the weight of their offspring before slaughter was over 200 g higher. Given the lack of effective methods for immunoprophylaxis and treatment, methisoprinol supplementation can be an effective means of counteracting the effects of AMDV on persistently infected farms.


Assuntos
Vírus da Doença Aleutiana do Vison/efeitos dos fármacos , Doença Aleutiana do Vison/tratamento farmacológico , Doença Aleutiana do Vison/prevenção & controle , Antivirais/farmacologia , Inosina Pranobex/farmacologia , Doença Aleutiana do Vison/mortalidade , Vírus da Doença Aleutiana do Vison/genética , Animais , Fazendas , Feminino , Linfonodos/virologia , Vison/virologia , Baço/virologia , Replicação Viral/efeitos dos fármacos
5.
Virol J ; 16(1): 87, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266524

RESUMO

BACKGROUND: Human infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied. METHODS: Thirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells. RESULTS: Four potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P<0.05). Rg006-NA119V, rg006-NA246T or rg006-NA274Y showed comparable replication capacity to wild-type virus (except for rg006-NA274Y at 96 h, P<0.05). CONCLUSIONS: All 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of HPAI H7N9 to NAIs. The NAI-resistant mutations in HPAI H7N9, in most cases, did not reduce the replication ability of the virus in mammalian cells. Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/virologia , Replicação Viral/efeitos dos fármacos , Substituição de Aminoácidos , Animais , Galinhas , Cães , Farmacorresistência Viral/genética , Humanos , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Aviária , Células Madin Darby de Rim Canino , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Zanamivir/farmacologia
6.
BMC Infect Dis ; 19(1): 622, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307416

RESUMO

BACKGROUND: Cell-surface mucins are expressed in apical epithelial cells of the respiratory tract, and contribute a crucial part of the innate immune system. Despite anti-inflammatory or antiviral functions being revealed for certain cell-surface mucins such as MUC1, the roles of other mucins are still poorly understood, especially in viral infections. METHODS: To further identify mucins significant in influenza infection, we screened the expression of mucins in human nasal epithelial cells infected by H3N2 influenza A virus. RESULTS: We found that the expression of MUC15 was significantly upregulated upon infection, and specific only to active infection. While MUC15 did not interact with virus particles or reduce viral replication directly, positive correlations were observed between MUC15 and inflammatory factors in response to viral infection. Given that the upregulation of MUC15 was only triggered late into infection when immune factors (including cytokines, chemokines, EGFR and phosphorylated ERK) started to peak and plateau, MUC15 may potentially serve an immunomodulatory function later during influenza viral infection. CONCLUSIONS: Our study revealed that MUC15 was one of the few cell-surface mucins induced during influenza infection. While MUC15 did not interact directly with influenza virus, we showed that its increase coincides with the peak of immune activation and thus MUC15 may serve an immunomodulatory role during influenza infection.


Assuntos
Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/patologia , Mucinas/metabolismo , Animais , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Cães , Células Epiteliais/classificação , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Humanos , Influenza Humana/metabolismo , Células Madin Darby de Rim Canino , Mucinas/antagonistas & inibidores , Mucinas/genética , Cavidade Nasal/citologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Regulação para Cima , Replicação Viral/efeitos dos fármacos
7.
BMC Bioinformatics ; 20(1): 297, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159726

RESUMO

BACKGROUND: Host factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. In this context, controllability analyses aim to identify key regulating host factors of the infected cell's progression. This knowledge can be utilized in further biological analysis to understand disease dynamics and isolate proteins for study as drug target candidates. RESULTS: Both topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. Functional analysis finds overlap of results with previous siRNA studies of host factors involved in influenza replication, NF-kB pathway and infection relevance, and roles as interferon regulating genes. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets. CONCLUSIONS: Seasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year with a constant threat of pandemic infection. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. These results are beneficial to future studies of influenza virus, both experimental and computational, and provide evidence that the combination of topology and controllability analyses may be valuable for future efforts in drug target discovery.


Assuntos
Antivirais/farmacologia , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Interações Hospedeiro-Patógeno , Mapas de Interação de Proteínas , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/metabolismo , RNA Interferente Pequeno/metabolismo , Reprodutibilidade dos Testes , Replicação Viral/efeitos dos fármacos
8.
Nat Commun ; 10(1): 2184, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097716

RESUMO

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.


Assuntos
Antivirais/farmacologia , Ciclopirox/farmacologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Montagem de Vírus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Ciclopirox/química , Ciclopirox/uso terapêutico , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Hepatócitos/transplante , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , RNA Viral/metabolismo , Quimeras de Transplante , Resultado do Tratamento , Proteínas do Core Viral/química , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacos
9.
BMC Vet Res ; 15(1): 134, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064364

RESUMO

BACKGROUND: Duck viral hepatitis (DVH) is an acute disease of young ducklings with no effective veterinary drugs for treatment. Gynostemma pentaphyllum is a well-known traditional Chinese medicine that plays an important role in the treatment of various diseases. Gypenoside (GP), one of the main ingredients of Gynostemma pentaphyllum, was reported with good hepatoprotective effects. However, its low solubility limits its application in the clinics. To improve its solubility and bioactivity, a phosphorylated derivative of gypenoside (pGP) was prepared by the sodium trimetaphosphate-sodium tripolyphosphate (STMP-STPP) method. An infrared spectroscopy method was applied to analyse the structures of GP and pGP. Then, a methyl thiazolyl tetrazolium (MTT) colorimetric assay was applied to study the hepatocyte protective efficacy of these two drugs against duck hepatitis A virus type 1 (DHAV-1) infection, and qPCR, TUNEL labelling and flow cytometry methods were used to study the relevant hepatocyte protective in vitro. RESULTS: The infrared spectroscopy detection results showed that the phosphorylation modification of GP was successful. The MTT colorimetric assay results showed that both GP and pGP possessed good hepatocyte protective efficacy in vitro, and pGP performed better than GP when the drug was added before or after virus inoculation. Furthermore, the qPCR results revealed that both drugs could effectively inhibit the adsorption (when adding GP and pGP pre-virus inoculation), replication and release of DHAV-1, and the viral inhibition rate of pGP was greater than that of GP. The subsequent TUNEL labelling and flow cytometry assays showed that both GP and pGP could significantly inhibit duck embryo hepatocyte apoptosis induced by DHAV-1, and the inhibition effect of pGP was much stronger than that of GP. CONCLUSIONS: GP exerts good hepatocyte protective efficacy not only by inhibiting the proliferation of DHAV-1 but also by inhibiting duck embryonic hepatocyte apoptosis induced by DHAV-1, and phosphorylation modification significantly improves the antiviral and the anti-apoptotic effects of GP. Therefore, pGP has the potential to be developed into a novel drug against DHAV-1 infection.


Assuntos
Vírus da Hepatite do Pato/efeitos dos fármacos , Animais , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Patos , Gynostemma/química , Hepatite Viral Animal/tratamento farmacológico , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Fosforilação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Replicação Viral/efeitos dos fármacos
10.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058822

RESUMO

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4-7 days post-vaccination, the only alternative method to control the spread of FMD virus (FMDV) during outbreaks is the application of antiviral agents. Hence, it is important to identify effective antiviral agents against FMDV infection. In this study, we found that mizoribine has potent antiviral activity against FMDV replication in IBRS-2 cells. A time-of-drug-addition assay demonstrated that mizoribine functions at the early stage of replication. Moreover, mizoribine also showed antiviral effect on FMDV in vivo. In summary, these results revealed that mizoribine could be a potential antiviral drug against FMDV.


Assuntos
Antivirais/administração & dosagem , Vírus da Febre Aftosa/fisiologia , Febre Aftosa/tratamento farmacológico , Ribonucleosídeos/administração & dosagem , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Surtos de Doenças , Febre Aftosa/epidemiologia , Febre Aftosa/virologia , Vírus da Febre Aftosa/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Camundongos , Ribonucleosídeos/química , Ribonucleosídeos/farmacologia , Suínos , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
11.
Nat Commun ; 10(1): 2265, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118422

RESUMO

Hepatitis delta virus (HDV) depends on the helper function of hepatitis B virus (HBV), which provides the envelope proteins for progeny virus secretion. Current infection-competent cell culture models do not support assembly and secretion of HDV. By stably transducing HepG2 cells with genes encoding the NTCP-receptor and the HBV envelope proteins we produce a cell line (HepNB2.7) that allows continuous secretion of infectious progeny HDV following primary infection. Evaluation of antiviral drugs shows that the entry inhibitor Myrcludex B (IC50: 1.4 nM) and interferon-α (IC50: 28 IU/ml, but max. 60-80% inhibition) interfere with primary infection. Lonafarnib inhibits virus secretion (IC50: 36 nM) but leads to a substantial intracellular accumulation of large hepatitis delta antigen and replicative intermediates, accompanied by the induction of innate immune responses. This work provides a cell line that supports the complete HDV replication cycle and presents a convenient tool for antiviral drug evaluation.


Assuntos
Antivirais/farmacologia , Vírus Delta da Hepatite/efeitos dos fármacos , Proteínas do Envelope Viral/metabolismo , Replicação Viral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Vírus da Hepatite B/metabolismo , Vírus Delta da Hepatite/fisiologia , Antígenos da Hepatite delta/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Concentração Inibidora 50
12.
Drug Des Devel Ther ; 13: 1059-1068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040643

RESUMO

Introduction: In this study, we report on the development of an effective delivery system for siRNAs; a novel cell-penetrating peptide (CPP), T9(dR), obtained from transportan (TP), was used for in vivo and in vitro testing. Methods: In this study, toxicity of T9(dR) and TP and efficient delivery of siRNA were tested in 293T, MDCK, RAW, and A549 cells. Furthermore, T9(dR)- and TP-delivered siRNAs against nucleoprotein (NP) gene segment of influenza virus (siNP) were studied in both cell lines and mice. Results: Gel retardation showed that T9(dR) effectively condensed siRNA into nanoparticles sized between 350 and 550 nm when the mole ratio of T9(dR) to siRNA was ≥4:1. In vitro studies demonstrated that T9(dR) successfully delivered siRNA with low cellular toxicity into several cell lines. It was also observed that T9(dR)-delivered siRNAs inhibited replication of influenza virus more efficiently as compared to that delivered by TP into the MDCK and A549 cells. It was also noticed that when given a combined tail vein injection of siNP and T9(dR) or TP, all mice in the 50 nmol siNP group infected with PR8 influenza virus survived and showed weight recovery at 2 weeks post-infection. Conclusion: This study indicates that T9(dR) is a promising siRNA delivery tool with potential application for nucleotide drug delivery.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Galanina/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/crescimento & desenvolvimento , RNA Interferente Pequeno/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Replicação Viral/efeitos dos fármacos , Venenos de Vespas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Galanina/química , Células Madin Darby de Rim Canino , RNA Interferente Pequeno/química , Proteínas Recombinantes de Fusão/química , Venenos de Vespas/química
13.
Eur J Med Chem ; 176: 431-455, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128447

RESUMO

Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia®, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Inibidores de Serino Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Vírus da Dengue/genética , Vírus da Dengue/crescimento & desenvolvimento , Descoberta de Drogas , Humanos , Inibidores de Serino Proteinase/química , Replicação Viral/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-30929566

RESUMO

Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5'-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC50 = 4.6 µM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC50 = 10 µM), while the activity was abolished with the corresponding 5'-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pirazolonas/química , Vírus da Dengue/efeitos dos fármacos , Desenho de Drogas , Hepacivirus/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Influenzavirus A/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Estrutura Molecular , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
15.
Vet Microbiol ; 231: 63-70, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30955825

RESUMO

Porcine reproductive and respiratory syndrome (PRRS) is a severe respiratory disease that leads to huge economic losses in the pig industry throughout the world. Although there are several vaccines available, the protective efficacy is limited. Therefore, new control strategies to prevent PRRS virus (PRRSV) infection are urgently required. We have previously reported that CH25H and 25HC can significantly inhibit the replication of PRRSV by preventing viral entry. In the present study, we found that 25HC with a low IC50 value significantly decreased the replication of different PRRSV strains, and increased the production of IL-1ß and IL-8 in porcine primary alveolar macrophages and the lung tissue. In pigs challenged with highly pathogenic PRRSV, treatment with 25HC was associated with an obvious reduction in the level of viremia and viral load in lung samples and nasal swabs, as well as decreased lung injury and an increased survival rate. These findings suggest that 25HC could be a promising antiviral drug against PRRSV in the future.


Assuntos
Antivirais/farmacologia , Hidroxicolesteróis/farmacologia , Síndrome Respiratória e Reprodutiva Suína/tratamento farmacológico , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Linhagem Celular , Concentração Inibidora 50 , Interleucina-1beta/imunologia , Interleucina-8/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Suínos , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Replicação Viral/efeitos dos fármacos
16.
Expert Rev Clin Pharmacol ; 12(5): 389-396, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31017494

RESUMO

INTRODUCTION: The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut. Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies. Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inflamação/tratamento farmacológico , Doença Crônica , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Sobrevida , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
17.
Eur J Med Chem ; 171: 401-419, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928711

RESUMO

GSK3082 - a hepatitis C virus RNA polymerase inhibitor - and a series of analogues with structural diversity at the 5-position were prepared from a 2,2,4,5-tetrasubstituted pyrrolidine obtained with a well-defined stereochemistry from the 1,3-dipolar cycloaddition of the chiral imino ester derived from leucine tert-butyl ester and (R)-2,3-O-isopropylideneglyceraldehyde with methyl acrylate. The chiral 2,2-dimethyl-1,3-dioxolane moiety provided by the glyceraldehyde served as a synthetic equivalent for different substituents and functional groups and these transformations usually required mild reaction conditions and simple work-up procedures. The inhibitory activity of the resulting GSK3082 analogues was studied in vitro in a cell-based assay of the subgenomic HCV RNA replication system. Some of the analogues showed good inhibitory activity with IC50 values in the nanomolar concentration range.


Assuntos
Antivirais/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , RNA Polimerases Dirigidas por DNA/metabolismo , Relação Dose-Resposta a Droga , Hepacivirus/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
18.
Nat Microbiol ; 4(7): 1196-1207, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936483

RESUMO

Numerous human APOBEC3 cytidine deaminases have proven to be, inter alia, host cell restriction factors for retroviruses and hepadnaviruses. Although they can bind to genomic RNA and become encapsidated, they are only catalytically active on single-stranded DNA. As there are many cellular deoxyribonucleases (DNases), we hypothesized that a parallel could be struck between APOBEC3 and DNases. For human hepatitis B virus (HBV), we show that DNase I can considerably reduce the virion genome copy number from a variety of transfected or infected cells. DNASE1 is overexpressed and encapsidated in HBV particles in vitro in hypoxic environments and in vivo in cirrhotic patient livers as well as in the serum of infected patients. The use of CoCl2 and dimethyloxalylglycine, mimetic agents used to induce hypoxia by inhibiting prolyl hydroxylase enzymes that stabilize hypoxia-inducible factor (HIF)-1α, showed that the formation of HIF-1α/HIF-1ß heterodimers results in the induction of DNASE1. Indeed, transfection with HIF-1α and HIF-1ß expression constructs upregulated DNASE1. These findings suggest that human DNase I can impact HBV replication through the catabolism of the DNA genome within the capsid. The activity of DNases in general may explain in part the high frequency of empty or 'light' hepatitis B virions observed in vivo.


Assuntos
Desoxirribonuclease I/metabolismo , Vírus da Hepatite B/fisiologia , Hipóxia , Replicação Viral , Linhagem Celular , Cobalto/farmacologia , DNA Viral/metabolismo , Desoxirribonuclease I/genética , Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatite B/enzimologia , Antígenos do Núcleo do Vírus da Hepatite B/metabolismo , Humanos , Hipóxia/induzido quimicamente , Fator 1 Induzível por Hipóxia/metabolismo , Cirrose Hepática/enzimologia , Mutação , Vírion/metabolismo , Replicação Viral/efeitos dos fármacos
19.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31032814

RESUMO

In humans, Zika virus and viral RNA have been detected in semen up to 2.2 months and 6 months post infection (pi), respectively. Although the contribution of sexual transmission to the spread of ZIKV is too low to sustain an outbreak, it can increase the risk of infection and the epidemic size as well as prolong the duration of an outbreak. In this study, we explored the potential of antivirals to serve as an effective strategy to prevent sexual transmission. Male AG129 mice infected with a ZIKV isolate from Suriname were treated with the nucleoside analog, 7-deaza-2'-C-methyladenosine (7DMA), that was previously shown to be efficacious in reducing ZIKV viremia and delaying ZIKV-induced disease in mice. Following treatment, viral RNA and infectious virus titers were consistently reduced in the male reproductive organs compared to vehicle-treated mice. This reduction of ZIKV loads in the testis was confirmed by the detection of lower levels of ZIKV antigens. Our data illustrate the value of this mouse model to validate the efficacy of new potential ZIKV drugs at the level of the male reproductive system.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Replicação Viral/efeitos dos fármacos , Infecção por Zika virus/virologia , Zika virus/efeitos dos fármacos , Zika virus/enzimologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Carga Viral/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/patologia
20.
Microb Pathog ; 131: 227-233, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30943433

RESUMO

Baicalein, an isolate of secutellaria baicalensis is known for its anti-inflammatory activity. In the present study, 12-triazole derivatives of baicalein were synthesized and evaluated against RSV infected BEAS-2B cells in vitro and in mice model in vivo. The preventive effect of most active compound 5f against RSV infection was studied in detail. The compound 5f treatment increased IFN-ß1 expression in BEAS-2B cells infected with RSV. In BEAS-2B cells treatment with compound 5f inhibited RSV-induced secretion of interleukin-6 and -8 cytokines. It decreased RSV-induced nitric oxide & malondialdehyde production and inhibited the RSV-mediated activation of NF-κB, COX-2, Stat3 and MAPK. The p38 phosphorylation was enhanced significantly in RSV infected cells by compound 5f pre-treatment. RT-qPCR showed that compound 5f treatment of the RSV-infected mice significantly (P < 0.05) decreased viral load through reduction in the viral replication. In the mice model of RSV-infection compound 5f treatment decreased interleukin-6, -8 and tumor necrosis factor-α expression. The level of MPO, nitric oxide and malondialdehyde was also decreased significantly by compound 5f in the RSV infected mice BALF. It also reduced the infiltration of neutrophils and lymphocytes in the BALF of RVS-infected mice. In summary, compound 5f inhibits RSV-infection and prevents pulmonary airway inflammation through the activation of IFN signalling pathway.


Assuntos
Flavanonas/farmacologia , Estresse Oxidativo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Infecções Respiratórias/prevenção & controle , Triazóis/farmacologia , Animais , Citocinas/metabolismo , Feminino , Flavanonas/síntese química , Interferon beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Pneumonia/virologia , Infecções Respiratórias/virologia , Ribavirina/farmacologia , Fator de Transcrição STAT3/metabolismo , Triazóis/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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