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1.
Viruses ; 11(2)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791582

RESUMO

Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against any of these pathogens. We here discuss the feasibility of developing a broad-spectrum antiviral treatment against these diarrhea-causing viruses. This review focuses on the viral polymerase as an antiviral target, as this is the most conserved viral protein among the diverse viral families to which these viruses belong to. We describe the functional and structural similarities of the different viral polymerases, the antiviral effect of reported polymerase inhibitors and highlight common features that might be exploited in an attempt of designing such pan-polymerase inhibitor.


Assuntos
Antivirais/isolamento & purificação , Diarreia/tratamento farmacológico , Diarreia/virologia , Gastroenterite/tratamento farmacológico , Gastroenterite/virologia , RNA Replicase/metabolismo , Infecções por Adenovirus Humanos/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Vírus de DNA/efeitos dos fármacos , Vírus de DNA/enzimologia , Humanos , Norovirus/efeitos dos fármacos , Norovirus/enzimologia , Inibidores da Síntese de Ácido Nucleico/isolamento & purificação , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/enzimologia , Rotavirus/efeitos dos fármacos , Rotavirus/enzimologia , Infecções por Rotavirus/tratamento farmacológico
2.
Int J Mol Sci ; 19(8)2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042322

RESUMO

Since being first described more than 60 years ago, Na,K-ATPase has been extensively studied, while novel concepts about its structure, physiology, and biological roles continue to be elucidated. Cardiac glycosides not only inhibit the pump function of Na,K-ATPase but also activate intracellular signal transduction pathways, which are important in many biological processes. Recently, antiviral effects have been described as a novel feature of Na,K-ATPase inhibition with the use of cardiac glycosides. Cardiac glycosides have been reported to be effective against both DNA viruses such as cytomegalovirus and herpes simplex and RNA viruses such as influenza, chikungunya, coronavirus, and respiratory syncytial virus, among others. Consequently, cardiac glycosides have emerged as potential broad-spectrum antiviral drugs, with the great advantage of targeting cell host proteins, which help to minimize resistance to antiviral treatments, making them a very promising strategy against human viral infections. Here, we review the effect of cardiac glycosides on viral biology and the mechanisms by which these drugs impair the replication of this array of different viruses.


Assuntos
Antivirais/farmacologia , Glicosídeos Cardíacos/farmacologia , Inibidores Enzimáticos/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Infecções por Vírus de DNA/tratamento farmacológico , Vírus de DNA/efeitos dos fármacos , Humanos , Infecções por Vírus de RNA/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Transdução de Sinais
3.
Bioorg Med Chem ; 26(12): 3596-3609, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29880251

RESUMO

The importance of phosphonoamidate prodrugs (ProTides) of acyclic nucleoside phosphonate (ANPs) is highlighted by the approval of Tenofovir Alafenamide Fumarate for the treatment of HIV and HBV infections. In the present paper we are reporting an expedient, one-pot, two-steps synthesis of allyl phosphonoamidates and diamidates that offers a time saving strategy when compared to literature methods. The use of these substrates in the cross metathesis reactions with alkenyl functionalised thymine and uracil nucleobases is reported. ANPs prodrugs synthesized via this methodology were evaluated for their antiviral activities against DNA and RNA viruses. It is anticipated that the use of 5,6,7,8-tetrahydro-1-napthyl as aryloxy moiety is capable to confer antiviral activity among a series of otherwise inactive uracil ProTides.


Assuntos
Antivirais/síntese química , Organofosfonatos/química , Pró-Fármacos/síntese química , Antivirais/sangue , Antivirais/farmacologia , Linhagem Celular , Vírus de DNA/efeitos dos fármacos , Estabilidade de Medicamentos , Humanos , Nucleosídeos/química , Organofosfonatos/sangue , Organofosfonatos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Vírus de RNA/efeitos dos fármacos , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 26(12): 3065-3075, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29853341

RESUMO

Isoxazole compounds exhibit a wide spectrum of targets and broad biological activities. Developing compounds with heterocycle rings has been one of the trends. The integration of isoxazole ring can offer improved physical-chemical properties. Because of the unique profiles, isoxazole ring becomes a popular moiety in compounds design. In this review article, the major focus has been paid to the applications of isoxazole compounds in treating multiple diseases, including anticancer, antimicrobial, anti-inflammatory, etc. Strategies for compounds design for preclinical, clinical, and FDA approved drugs were discussed. Also, the emphasis has been addressed to the future perspectives and trend for the application.


Assuntos
Química Farmacêutica , Isoxazóis/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bactérias/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos
5.
Int J Mol Sci ; 19(3)2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29522483

RESUMO

For three decades now, ionic liquids (ILs), organic salts comprising only ions, have emerged as a new class of pharmaceuticals. Although recognition of the antimicrobial effects of ILs is growing rapidly, there is almost nothing known about their possible virucidal activities. This probably reflects the paucity of understanding virus inactivation. In this study, we performed a systematic analysis to determine the effect of specific structural motifs of ILs on three different biological test systems (viruses, bacteria and enzymes). Overall, the effects of 27 different ILs on two non-enveloped and one enveloped virus (P100, MS2 and Phi6), two Gram negative and one Gram positive bacteria (E. coli, P. syringae and L. monocytogenes) and one enzyme (Taq DNA polymerase) were investigated. Results show that while some ILs were virucidal, no clear structure activity relationships (SARs) could be identified for the non-enveloped viruses P100 and MS2. However, for the first time, a correlation has been demonstrated between the effects of ILs on enveloped viruses, bacteria and enzyme inhibition. These identified SARs serve as a sound starting point for further studies.


Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Líquidos Iônicos/farmacologia , Vírus de RNA/efeitos dos fármacos , Antivirais/química , Escherichia coli/efeitos dos fármacos , Humanos , Líquidos Iônicos/química , Listeria monocytogenes/efeitos dos fármacos , Pseudomonas syringae/efeitos dos fármacos , Relação Estrutura-Atividade , Taq Polimerase/efeitos dos fármacos
6.
Pestic Biochem Physiol ; 144: 10-18, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29463403

RESUMO

Pathogens and pesticides are likely to co-occur in honeybee hives, but much remains to be investigated regarding their potential interactions. Here, we first investigated the metabolisation kinetics of thiamethoxam in chronically fed honeybees. We show that thiamethoxam, at a dose of 0.25ng/bee/day, is quickly and effectively metabolised into clothianidin, throughout a 20day exposure period. Using a similar chronic exposure to pesticide, we then studied, in a separate experiment, the impact of thiamethoxam and Chronic bee paralysis virus (CBPV) co-exposure in honeybees. The honeybees were exposed to the virus by contact, mimicking the natural transmission route in the hive. We demonstrate that a high dose of thiamethoxam (5.0ng/bee/day) can cause a synergistic increase in mortality in co-exposed honeybees after 8 to 10days of exposure, with no increase in viral loads. At a lower dose (2.5ng/bee/day), there was no synergistic increase of mortality, but viral loads were significantly higher in naturally dead honeybees, compared with sacrificed honeybees exposed to the same conditions. These results show that the interactions between pathogens and pesticides in honeybees can be complex: increasing pesticide doses may not necessarily be linked to a rise in viral loads, suggesting that honeybee tolerance to the viral infection might change with pesticide exposure.


Assuntos
Abelhas/virologia , Neonicotinoides/metabolismo , Nitrocompostos/metabolismo , Oxazinas/metabolismo , Praguicidas/metabolismo , Vírus de RNA/efeitos dos fármacos , Tiazóis/metabolismo , Animais , Abelhas/fisiologia , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Guanidinas/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Oxazinas/farmacologia , Praguicidas/farmacologia , Reto/metabolismo , Tiametoxam , Tiazóis/farmacologia
7.
Antivir Chem Chemother ; 25(3): 90-93, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29172646

RESUMO

Objective To synthesize 3,7-dideazaneplanocin and evaluate its antiviral potential. Methods The target 3,7-dideazaneplanocin has been prepared in five steps from a readily available cyclopentenol. A thorough in vitro antiviral analysis was conducted versus both DNA and RNA viruses. Results A rational synthesis of 3,7-dideazaneplanocin was conceived and successfully pursued in such a way that it can be adapted to various analogs of 3,7-dideazaneplanocin. Using standard antiviral assays, no activity for 3,7-dideazaneplanocn was found. Conclusion Two structural features are necessary for adenine-based carbocyclic nucleosides (like neplanocin) for potential antiviral properties: (i) inhibition of S-adenosylhomocysteine hydrolase and/or (ii) C-5' activation via the mono-nucleotide. These two requisite adenine structural features to fit these criteria are not present in in the target 3,7-dideazaneplanocin: (i) an N-7 is necessary for inhibition of the hydrolase and the N-3 is claimed to be essential for phosphorylation at C-5'. Thus, it is not surprising that 3,7-dideazaneplaoncin lacked antiviral properties.


Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Piridonas/farmacologia , Vírus de RNA/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hidrolases/antagonistas & inibidores , Hidrolases/metabolismo , Testes de Sensibilidade Microbiana , Conformação Molecular , Piridonas/síntese química , Piridonas/química
8.
Viruses ; 9(11)2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29149077

RESUMO

The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti-viral drug design.


Assuntos
Evolução Molecular , Quase-Espécies/genética , Vírus de RNA/genética , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Simulação por Computador , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Farmacorresistência Viral Múltipla/genética , Humanos , Quase-Espécies/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/patogenicidade , RNA Viral/genética , Viroses/virologia
9.
Plant Signal Behav ; 12(6): e1338223, 2017 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-28594275

RESUMO

Reactive oxygen species (ROS), including superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical, act as signaling molecules to transduce biotic and abiotic stimuli into stress adaptations in plants. A respiratory burst oxidase homolog B of Nicotiana benthamiana (NbRBOHB) is responsible for O2- production to inhibit pathogen infection during plant innate immunity. RBOH-derived O2- can be immediately converted into H2O2 by the action of superoxide dismutase. Interestingly, we recently showed that red clover necrotic mosaic virus (RCNMV), a plant positive-strand RNA [(+)RNA] virus, hijacks the host's ROS-generating machinery during infection. An RCNMV replication protein associates with NbRBOHB and triggers intracellular ROS bursts. These bursts are required for robust viral RNA replication. However, what types of ROS are required for viral replication is currently unknown. Here, we found that RCNMV replication was sensitive to an O2- scavenger but insensitive to an H2O2 scavenger. Interestingly, replication of another plant (+)RNA virus, brome mosaic virus, was sensitive to both types of scavengers. These results indicate a virus-specific pattern requirement of O2- and H2O2 for (+)RNA virus replication and suggest a conserved nature of the roles of ROS in (+)RNA virus replication.


Assuntos
Peróxido de Hidrogênio/metabolismo , Vírus de Plantas/fisiologia , Vírus de RNA/fisiologia , Superóxidos/metabolismo , Tabaco/virologia , Replicação Viral/fisiologia , Depuradores de Radicais Livres/farmacologia , Vírus de Plantas/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Tabaco/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
10.
Antiviral Res ; 144: 196-204, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28624461

RESUMO

At a noncytotoxic concentration, emetine was found to inhibit replication of DNA viruses [buffalopoxvirus (BPXV) and bovine herpesvirus 1 (BHV-1)] as well as RNA viruses [peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV)]. Using the time-of-addition and virus step-specific assays, we showed that emetine treatment resulted in reduced synthesis of viral RNA (PPRV and NDV) and DNA (BPXV and BHV-1) as well as inhibiting viral entry (NDV and BHV-1). In addition, emetine treatment also resulted in decreased synthesis of viral proteins. In a cell free endogenous viral polymerase assay, emetine was found to significantly inhibit replication of NDV, but not BPXV genome, suggesting that besides directly inhibiting specific viral polymerases, emetine may also target other factors essentially required for efficient replication of the viral genome. Moreover, emetine was found to significantly inhibit BPXV-induced pock lesions on chorioallantoic membrane (CAM) along with associated mortality of embryonated chicken eggs. At a lethal dose 50 (LD50) of 126.49 ng/egg and at an effective concentration 50 (EC50) of 3.03 ng/egg, the therapeutic index of the emetine against BPXV was determined to be 41.74. Emetine was also found to significantly delay NDV-induced mortality in chicken embryos associated with reduced viral titers. Further, emetine-resistant mutants were not observed upon long-term (P = 25) sequential passage of BPXV and NDV in cell culture. Collectively, we have extended the effective antiviral activity of emetine against diverse groups of DNA and RNA viruses and propose that emetine could provide significant therapeutic value against some of these viruses without inducing an antiviral drug-resistant phenotype.


Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Emetina/farmacologia , Vírus de RNA/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Bovinos , Cercopithecus aethiops , Embrião de Galinha , Vírus de DNA/fisiologia , Farmacorresistência Viral , Vírus de RNA/fisiologia
11.
J Gen Virol ; 98(5): 946-954, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28555543

RESUMO

Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus. No significant cellular toxicity was observed at the effective concentrations. Animal studies showed an improved survival rate in BALB/c mice that received intranasal FA-613 treatments against a lethal dose infection of A/HK/415742Md/2009 (H1N1). Further cell-based assays indicated that FA-613 interfer with the de novo pyrimidine biosynthesis pathway by targeting the dihydroorotate dehydrogenase. Surprisingly, FA-613 lost its antiviral potency in the interferon-deficient Vero cell line, while maintaining its inhibitory activity in an interferon-competent cell line which showed elevated expression of host antiviral genes when infected in the presence of FA-613. Further investigation of the specific connection between pyrimidine synthesis inhibition and the induction of host innate immunity might aid clinical development of this type of drug in antiviral therapies. Therefore, in acute cases of respiratory tract infections, when rapid diagnostics of the causative agent are not readily available, an antiviral drug with properties like FA-613 could prove to be very valuable.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Interferons/metabolismo , Pirimidinas/biossíntese , Vírus de RNA/efeitos dos fármacos , Animais , Linhagem Celular , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Coronavírus da Síndrome Respiratória do Oriente Médio , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Vírus de RNA/crescimento & desenvolvimento , Vírus de RNA/imunologia , Análise de Sobrevida
12.
J Virol Methods ; 246: 51-57, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28359770

RESUMO

Studies were conducted to determine the performance of four dyes in assessing antiviral activities of compounds against three RNA viruses with differing cytopathogenic properties. Dyes included alamarBlue® measured by absorbance (ALB-A) and fluorescence (ALB-F), neutral red (NR), Viral ToxGlo™ (VTG), and WST-1. Viruses were chikungunya, dengue type 2, and Junin, which generally cause 100, 80-90, and 50% maximal cytopathic effect (CPE), respectively, in Vero or Vero 76 cells Compounds evaluated were 6-azauridine, BCX-4430, 3-deazaguanine, EICAR, favipiravir, infergen, mycophenolic acid (MPA), ribavirin, and tiazofurin. The 50% virus-inhibitory (EC50) values for each inhibitor and virus combination did not vary significantly based on the dye used. However, dyes varied in distinguishing the vitality of virus-infected cultures when not all cells were killed by virus infection. For example, VTG uptake into dengue-infected cells was nearly 50% when visual examination showed only 10-20% cell survival. ALB-A measured infected cell viability differently than ALB-F as follows: 16% versus 32% (dengue-infected), respectively, and 51% versus 72% (Junin-infected), respectively. Cytotoxicity (CC50) assays with dyes in uninfected proliferating cells produced similar CC50 values for EICAR (1.5-8.9µM) and MPA (0.8-2.5µM). 6-Azauridine toxicity was 6.1-17.5µM with NR, VTG, and WST-1, compared to 48-92µM with ALB-A and ALB-F (P<0.001). Curiously, the CC50 values for 3-deazaguanine were 83-93µM with ALB-F versus 2.4-7.0µM with all other dyes including ALB-A (P<0.001). Overall, ALB minimized the toxicities detected with these two inhibitors. Because the choice of dyes affected CC50 values, this impacted on the resulting in vitro selectivity indexes (calculated as CC50/EC50 ratio).


Assuntos
Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Corantes , Efeito Citopatogênico Viral , Vírus de RNA/efeitos dos fármacos , Vírus/efeitos dos fármacos , Animais , Cercopithecus aethiops , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/patogenicidade , Vírus Chikungunya/fisiologia , Corantes/química , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/patogenicidade , Vírus da Dengue/fisiologia , Vírus Junin/efeitos dos fármacos , Vírus Junin/patogenicidade , Vírus Junin/fisiologia , Oxazinas , Vírus de RNA/patogenicidade , Vírus de RNA/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos , Xantenos
13.
Hepatol Int ; 11(3): 277-285, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28361300

RESUMO

BACKGROUND AND AIMS: Recently, Sofosbuvir was launched in India at affordable cost. We conducted a real-life study to determine the efficacy and safety of Sofosbuvir plus Ribavirin, with and without peginterferon-alfa 2a, in patients with chronic hepatitis C (CHC) genotype 3, the commonest genotype in South Asia. METHODS: This study included data of CHC patients from 11 sites in northern India between March 2015 and December 2015 (n = 1203). Patients with CHC genotype 3 (n = 931), who were treated with either Sofosbuvir 400 mg plus weight-based Ribavirin, daily ×24 weeks (n = 432) (dual therapy), or Peginterferon-α2a 180 mcg weekly, Sofosbuvir 400 mg plus weight-based Ribavirin, daily ×12 weeks (n = 499) (triple therapy) were included for analysis. Primary outcome was the proportion of patients achieving sustained viral response at 12 weeks post-therapy. RESULTS: The overall SVR rates were 91 and 92% in the dual and triple therapy arms, respectively. The SVR rates in treatment experienced were 67 and 74% versus 93 and 96% in naïve patients, on the dual and triple therapy arms, respectively. The SVR rates of cirrhotics were 73 and 75% on the dual and triple treatment arms, respectively. The SVR rates were low in the experienced cirrhotic patients: 44% (dual therapy) and 58% (triple therapy). Common adverse events were fatigue, headache, and myalgia. CONCLUSION: Both dual and triple therapy regimes resulted in SVR rates of >95% in CHC genotype 3 who were naive non-cirrhotics. However, the SVR rates were low in treatment-experienced cirrhotics.


Assuntos
Quimioterapia Combinada/métodos , Hepacivirus/genética , Interferon-alfa/farmacologia , Polietilenoglicóis/farmacologia , Ribavirina/farmacologia , Sofosbuvir/farmacologia , Adulto , Antivirais/uso terapêutico , Ásia/epidemiologia , Quimioterapia Combinada/tendências , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Índia/epidemiologia , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Vírus de RNA/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
14.
Antiviral Res ; 142: 1-11, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28286234

RESUMO

Viral infection induces translocation of the nucleolar protein GLTSCR2 from the nucleus to the cytoplasm, resulting in attenuation of the type I interferon IFN-ß. Addressing the role of GLTSCR2 in viral replication, we detect that knocking down GLTSCR2 by shRNAs results in significant suppression of viral replication in mammalian and chicken cells. Injection of chicken embryo with the GLTSCR2-specific shRNA-1370 simultaneously or 24 h prior to infection with Newcastle disease virus (NDV) substantially reduces viral replication in chicken embryo fibroblasts. Injection of shRNA-1370 into chicken embryo also reduces the replication of avian influenza virus (AIV). In contrast, GLTSCR2-derived protein G4-T, forming α-helical dimers, increases replication of seven various DNA and RNA viruses in cells. Our studies reveal that alteration of the function of cellular GLTSCR2 plays a role in supporting viral replication. GLTSCR2 should be seriously considered as a therapeutic target for developing broad spectrum antiviral agents to effectively control viral infection.


Assuntos
Antivirais/farmacologia , Proteínas Supressoras de Tumor/efeitos dos fármacos , Proteínas Supressoras de Tumor/fisiologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia , Animais , Linhagem Celular , Cercopithecus aethiops , Embrião de Galinha , Vírus de DNA/efeitos dos fármacos , Cães , Fibroblastos/virologia , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Interferon Tipo I/metabolismo , Interferon-alfa/metabolismo , Células Madin Darby de Rim Canino , Doença de Newcastle/virologia , Vírus da Doença de Newcastle/efeitos dos fármacos , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/fisiologia , Conformação Proteica em alfa-Hélice/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , RNA Interferente Pequeno/genética , Proteínas Recombinantes , Proteínas Supressoras de Tumor/genética , Células Vero , Replicação Viral/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/fisiologia
15.
Sci Rep ; 7: 41029, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28106111

RESUMO

Hydrogen sulfide is an important endogenous mediator that has been the focus of intense investigation in the past few years, leading to the discovery of its role in vasoactive, cytoprotective and anti-inflammatory responses. Recently, we made a critical observation that H2S also has a protective role in paramyxovirus infection by modulating inflammatory responses and viral replication. In this study we tested the antiviral and anti-inflammatory activity of the H2S slow-releasing donor GYY4137 on enveloped RNA viruses from Ortho-, Filo-, Flavi- and Bunyavirus families, for which there is no FDA-approved vaccine or therapeutic available, with the exception of influenza. We found that GYY4137 significantly reduced replication of all tested viruses. In a model of influenza infection, GYY4137 treatment was associated with decreased expression of viral proteins and mRNA, suggesting inhibition of an early step of replication. The antiviral activity coincided with the decrease of viral-induced pro-inflammatory mediators and viral-induced nuclear translocation of transcription factors from Nuclear Factor (NF)-kB and Interferon Regulatory Factor families. In conclusion, increasing cellular H2S is associated with significant antiviral activity against a broad range of emerging enveloped RNA viruses, and should be further explored as potential therapeutic approach in relevant preclinical models of viral infections.


Assuntos
Antivirais/farmacologia , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Vírus de RNA/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Citocinas/metabolismo , Humanos , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos
16.
Influenza Other Respir Viruses ; 11(1): 85-92, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27542891

RESUMO

AIM: Aspirin (acetylsalicylic acid) has been used for more than 115 years in medicine. Research exists to show that aspirin has antiviral effects in vitro, for example, by blocking influenza virus propagation via NF-κB inhibition when used at high concentrations and short-term incubation steps. The aim of this study was to confirm the antiviral activity of aspirin against influenza virus and further elucidate the activity of aspirin against other respiratory viruses. METHODS: Tests to detect antiviral activity were performed using plaque-reduction assays. Aspirin was administered to the virus-infected cell cultures one hour after infection. Prior to these assays, the non-cytotoxic concentrations of aspirin on cells used for propagation of the respective viruses were determined. RESULTS: Aspirin was found to be highly effective against influenza A H1N1 virus. The antiviral activity against further respiratory RNA viruses was less distinct. Respiratory syncytial virus was minimally inhibited. However, the activity of aspirin against rhinoviruses was more pronounced. Aspirin demonstrated antiviral activity against all human rhinoviruses (HRV), but the effect on members of the "major group" viruses, namely HRV14 and HRV39, was greater than on those of the "minor group," HRV1A and HRV2. CONCLUSIONS: These data demonstrate a specific antiviral activity of aspirin against influenza A virus and HRV. The mode of action against rhinoviruses is still unknown and requires further investigation, as does the possibility of aspirin being effective in vivo to treat the common cold.


Assuntos
Antivirais/farmacologia , Aspirina/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus de RNA/efeitos dos fármacos , Sistema Respiratório/virologia , Rhinovirus/efeitos dos fármacos , Enterovirus/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Ensaio de Placa Viral
17.
Bioorg Med Chem Lett ; 27(2): 139-142, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27979594

RESUMO

A series of 4-substituted 3,4-dihydropyrimidine-2-ones (DHPM) was synthesized, characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The compounds were evaluated in vitro for their antiviral activity against a broad range of DNA and RNA viruses, along with assessment for potential cytotoxicity in diverse mammalian cell lines. Compound 4m, which possesses a long lipophilic side chain, was found to be a potent and selective inhibitor of Punta Toro virus, a member of the Bunyaviridae. For Rift Valley fever virus, which is another Bunyavirus, the activity of 4m was negligible. DHPMs with a C-4 aryl moiety bearing halogen substitution (4b, 4c and 4d) were found to be cytotoxic in MT4 cells.


Assuntos
Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Pirimidinonas/farmacologia , Vírus de RNA/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/toxicidade , Bunyaviridae/efeitos dos fármacos , Gatos , Cercopithecus aethiops , Sulfato de Dextrana/farmacologia , Cães , Células HeLa , Humanos , Ácido Micofenólico/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/toxicidade , Ribavirina/farmacologia , Células Vero
18.
Wiad Lek ; 69(3 pt 2): 499-511, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27717933

RESUMO

THE AIM: The in-vitro antiviral activity of the "Virus Blocking Factor" (VBF), a combination of Pelargonium extract and Sambucus juice with addition of Betaglucan 1,3 / 1,6, Zincum gluconium, Acidum ascorbicum, was studied against human pathogenic viruses: Influenza A H1N1 (FluA H1N1), Rhinovirus B subtype 14 (HRV14), Respiratory Syncytial Virus (RSV), Parainfluenzavirus subtype 3 (Para 3), and Adenovirus C subtype 5 (Adeno 5). METHOD: Antiviral activity was assessed using plaque-reduction assays after adding the test substance post infection of the MDCK, HeLa and HEp-2 cells with the viruses. Ribavirin Virazol and - in case of Adenovirus an internal laboratory standard - were used as positive controls. Cytotoxic effects of VBF and VBF Control onto the virus permissive MDCK, HeLa and HEp-2 cells were examined. Non-toxic concentrations of VBF were determined by the Methylthiazoletetrazolium test (MTT-Test). RESULTS AND CONCLUSIONS: In all antiviral studies VBF showed (2.1%) a dose-dependent antiviral activity against FluA H1N1 and HRV14 at non-toxic concentrations. A very strong effect was demonstrated in concentrations of 2.5% and 1.25% where replication of H1N1 and HRV14 was nearly completely blocked. Dose-dependent antiviral activity was detectable against RSV in a concentration range of 1.25% to 0.63% of the test item. Due to toxic side effects of a 2.5% concentration at least a "minor effect" of about 30% (1.25% solution) against Para 3 infected HEp-2 cells could be determined. Concerning Adeno 5 not any antiviral activity could be demonstrated in all studies with all tested substance concentrations of VBF. VBF Control did not show any cytotoxicity and antiviral effects. Further research is needed to elucidate clinical effect of VBF.


Assuntos
Antivirais/farmacologia , Pelargonium/química , Sambucus/química , Viroses/tratamento farmacológico , Adenovírus Humanos/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Sucos de Frutas e Vegetais/análise , Humanos , Extratos Vegetais/química , Raízes de Plantas/química , Vírus de RNA/efeitos dos fármacos
19.
Viruses ; 8(10)2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27783035

RESUMO

Human cytomegalovirus is a ubiquitous ß-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.


Assuntos
Antivirais/farmacologia , Citomegalovirus/fisiologia , Podofilotoxina/farmacologia , Moduladores de Tubulina/farmacologia , Internalização do Vírus/efeitos dos fármacos , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Humanos , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia
20.
Nat Immunol ; 17(11): 1252-1262, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27595231

RESUMO

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.


Assuntos
Aminoacil-tRNA Sintetases/metabolismo , Resistência à Doença/imunologia , Interações Hospedeiro-Patógeno/imunologia , Viroses/imunologia , Viroses/metabolismo , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/genética , Animais , Antivirais/farmacologia , Modelos Animais de Doenças , Imunidade Inata , Camundongos , Camundongos Knockout , Peptídeos/farmacologia , Fosforilação , Ligação Proteica , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/metabolismo , Infecções por Vírus de RNA/virologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/imunologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Ubiquitinação , Viroses/virologia , Replicação Viral
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