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1.
Sci Rep ; 11(1): 19998, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620963

RESUMO

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Assuntos
Antivirais/metabolismo , COVID-19/tratamento farmacológico , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/farmacologia , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacologia , Amidas/efeitos adversos , Amidas/metabolismo , Amidas/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , COVID-19/metabolismo , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Cloroquina/metabolismo , Cloroquina/farmacologia , Desenho de Fármacos , Humanos , Redes e Vias Metabólicas , Simulação de Acoplamento Molecular , Nitrocompostos/efeitos adversos , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Pirazinas/efeitos adversos , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ribavirina/efeitos adversos , Ribavirina/metabolismo , Ribavirina/farmacologia , SARS-CoV-2/metabolismo , Tiazóis/efeitos adversos , Tiazóis/metabolismo , Tiazóis/farmacologia
2.
Front Cell Infect Microbiol ; 11: 746926, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604118

RESUMO

Due to lacking a proofreading mechanism in their RNA-dependent RNA polymerases (RdRp), RNA viruses generally possess high mutation frequencies, making them evolve rapidly to form viral quasispecies during serial passages in cells, especially treated with mutagens, like ribavirin. Canine distemper virus (CDV) belongs to the genus Morbillivirus. Its L protein functions as an RdRp during viral replication. In this study, a recombinant enhanced green fluorescence protein-tagged CDV (rCDV-eGFP) was rescued from its cDNA clone, followed by viral identification and characterization at passage-7 (P7). This recombinant was independently subjected to extra 40 serial passages (P8 to 47) in ribavirin- and non-treated cells. Two viral progenies, undergoing passages in ribavirin- and non-treated VDS cells, were named rCDV-eGFP-R and -N, respectively. Both progenies were simultaneously subjected to next-generation sequencing (NGS) at P47 for comparing their quasispecies diversities with each other. The rCDV-eGFP-R and -N showed 62 and 23 single-nucleotide mutations (SNMs) in individual antigenomes, respectively, suggesting that the ribavirin conferred a mutagenic effect on the rCDV-eGFP-R. The spectrum of 62 SNMs contained 26 missense and 36 silent mutations, and that of 23 SNMs was composed of 17 missense and 6 silent mutations. Neither the rCDV-eGFP-R nor -N exhibited nonsense mutation in individual antigenomes. We speculate that the rCDV-eGFP-R may contain at least one P47 sub-progeny characterized by high-fidelity replication in cells. If such a sub-progeny can be purified from the mutant swarm, its L protein would elucidate a molecular mechanism of CDV high-fidelity replication.


Assuntos
Vírus da Cinomose Canina , Animais , Vírus da Cinomose Canina/genética , Mutação , RNA Polimerase Dependente de RNA , Ribavirina/farmacologia , Inoculações Seriadas
3.
BMC Vet Res ; 17(1): 318, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34587973

RESUMO

BACKGROUND: Encephalomyocarditis virus (EMCV) infection can cause reproductive failure in sows and acute myocarditis and sudden death in piglets. It has caused huge economic losses to the global pig industry and that is why it is necessary to develop effective new treatment compounds. Zedoary turmeric oil has been used for treating myocarditis. Curcumol extracted from the roots of curcuma is one of the main active ingredient of zedoary turmeric oil. The anti-EMCV activity of curcumol along with the molecular mechanisms involved with a focus on IFN-ß signaling pathway was investigated in this study. METHOD: 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the maximum non-toxic concentration (MNTC), 50% cytotoxic concentration (CC50), maximum inhibition rate (MIR) and 50% effective concentration (EC50) against EMCV. Through EMCV load, the anti-viral effect of curcumol was quantitatively determined using real-time quantitative PCR (qPCR). The effect of curcumol on the expression of IFN-ß was investigated using real-time quantitative PCR and ELISA. Western blot was used to determine the amounts of MDA5, MAVS, TANK, IRF3 and P-IRF3 proteins in human embryonic kidney 293 T (HEK-293 T) cells infected with EMCV. RESULTS: The results of MTT showed that compared with the ribavirin positive control group, the maximum inhibition ratio (MIR) of curcumol was greater but the selection index (SI) value was much smaller than that of ribavirin. The results of qPCR showed that curcumol and ribavirin significantly reduced the replication of EMCV in HEK-293 T cells. The curcumol (0.025 mg/mL) treatment has significantly increased IFN-ß mRNA expression in the EMCV-infected HEK-293 T cells while ribavirin treatment did not. The results of ELISA showed that curcumol (0.025 mg/mL and 0.0125 mg/mL) has significantly increased the expression of IFN-ß protein in EMCV-infected HEK-293 T cells. The results of Western blot showed that curcumol can inhibit the degradation of TANK protein mediated by EMCV and promote the expression of MDA5 and P-IRF3, while the protein expression level of MAVS and IRF3 remain unchanged. CONCLUSION: Curcumol has biological activity against EMCV which we suggest that IFN-ß signaling pathway is one of its mechanisms.


Assuntos
Antivirais/farmacologia , Vírus da Encefalomiocardite/efeitos dos fármacos , Sesquiterpenos/farmacologia , Infecções por Cardiovirus/tratamento farmacológico , Infecções por Cardiovirus/virologia , Células HEK293 , Humanos , Interferon beta/efeitos dos fármacos , Interferon beta/metabolismo , Ribavirina/farmacologia , Sesquiterpenos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
4.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34342560

RESUMO

Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirin in cellulo. Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.


Assuntos
Antivirais/farmacologia , Cloroquina/farmacologia , Pirimetamina/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Hospedeiro Imunocomprometido , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Ribavirina/farmacologia
5.
J Gen Virol ; 102(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34242156

RESUMO

Bactrian camel hepatitis E virus (HEV) is a novel HEV belonging to genotype 8 (HEV-8) in the Orthohepevirus A species of the genus Hepevirus in the family Hepeviridae. HEV-8 cross-transmits to cynomolgus monkeys and has a potential risk for zoonotic infection. Until now, neither a cell-culture system to grow the virus nor a reverse genetics system to generate the virus has been developed. To generate replication-competent HEV-8 and to establish a cell-culture system, we synthesized capped genomic HEV-8 RNAs by in vitro transcription and used them to transfect into PLC/PRF/5 cells. A HEV-8 strain, HEV-8M2, was recovered from the capped HEV-8 RNA-transfected cell-culture supernatants and subsequently passaged in the cells, demonstrating that PLC/PRF/5 cells were capable of supporting the replication of the HEV-8, and that a cell-culture system for HEV-8 was successfully established. In addition to PLC/PRF/5 cells, A549 and Caco-2 cells appeared to be competent for the replication, but HepG2 C3/A, Vero, Hela S3, HEp-2C, 293T and GL37 cells were incompetent. The HEV-8M2 strain was capable of infecting cynomolgus monkeys by an intravenous inoculation, indicating that HEV-8 was infectious and again carried a risk for zoonotic infection. In contrast, HEV-8 did not infect nude rats and BALB/c nude mice, suggesting that the reservoir of HEV-8 was limited. In addition, the replication of the HEV-8M2 strain was efficiently abrogated by ribavirin but not by favipiravir, suggesting that ribavirin is a drug candidate for therapeutic treatment of HEV-8-induced hepatitis. The infectious HEV-8 produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of type E hepatitis.


Assuntos
Vírus da Hepatite E/genética , Vírus da Hepatite E/fisiologia , Hepatite E/virologia , Genética Reversa , Amidas/farmacologia , Animais , Antivirais/farmacologia , Proteínas do Capsídeo/análise , Linhagem Celular , Feminino , Genoma Viral , Vírus da Hepatite E/efeitos dos fármacos , Vírus da Hepatite E/patogenicidade , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Pirazinas/farmacologia , RNA Viral/genética , Ratos , Ribavirina/farmacologia , Transfecção , Replicação Viral/efeitos dos fármacos
6.
Nat Commun ; 12(1): 3766, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145268

RESUMO

Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Regulação da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 1 Nuclear Respiratório/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Ribavirina/farmacologia , Transdução de Sinais , Transcriptoma/genética
7.
Viruses ; 13(4)2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916702

RESUMO

Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium-revealed by the changing composition of the mutant spectrum-may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed.


Assuntos
Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C/virologia , Antivirais/farmacologia , COVID-19 , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Mutação , RNA Viral , Ribavirina/farmacologia , Análise de Sequência , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
8.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33827947

RESUMO

RNA viruses demonstrate a vast range of variants, called quasispecies, due to error-prone replication by viral RNA-dependent RNA polymerase. Although live attenuated vaccines are effective in preventing RNA virus infection, there is a risk of reversal to virulence after their administration. To test the hypothesis that high-fidelity viral polymerase reduces the diversity of influenza virus quasispecies, resulting in inhibition of reversal of the attenuated phenotype, we first screened for a high-fidelity viral polymerase using serial virus passages under selection with a guanosine analog ribavirin. Consequently, we identified a Leu66-to-Val single amino acid mutation in polymerase basic protein 1 (PB1). The high-fidelity phenotype of PB1-L66V was confirmed using next-generation sequencing analysis and biochemical assays with the purified influenza viral polymerase. As expected, PB1-L66V showed at least two-times-lower mutation rates and decreased misincorporation rates, compared to the wild type (WT). Therefore, we next generated an attenuated PB1-L66V virus with a temperature-sensitive (ts) phenotype based on FluMist, a live attenuated influenza vaccine (LAIV) that can restrict virus propagation by ts mutations, and examined the genetic stability of the attenuated PB1-L66V virus using serial virus passages. The PB1-L66V mutation prevented reversion of the ts phenotype to the WT phenotype, suggesting that the high-fidelity viral polymerase could contribute to generating an LAIV with high genetic stability, which would not revert to the pathogenic virus.IMPORTANCE The LAIV currently in use is prescribed for actively immunizing individuals aged 2 to 49 years. However, it is not approved for infants and elderly individuals, who actually need it the most, because it might prolong virus propagation and cause an apparent infection in these individuals, due to their weak immune systems. Recently, reversion of the ts phenotype of the LAIV strain currently in use to a pathogenic virus was demonstrated in cultured cells. Thus, the generation of mutations associated with enhanced virulence in LAIV should be considered. In this study, we isolated a novel influenza virus strain with a Leu66-to-Val single amino acid mutation in PB1 that displayed a significantly higher fidelity than the WT. We generated a novel LAIV candidate strain harboring this mutation. This strain showed higher genetic stability and no ts phenotype reversion. Thus, our high-fidelity strain might be useful for the development of a safer LAIV.


Assuntos
Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Vacinas contra Influenza , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/genética , Substituição de Aminoácidos , Animais , Antivirais/farmacologia , Cães , Farmacorresistência Viral , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Mutação , Fenótipo , Engenharia de Proteínas , RNA Polimerase Dependente de RNA/química , Ribavirina/farmacologia , Vacinas Atenuadas , Ensaio de Placa Viral , Proteínas Virais/química , Proteínas Virais/metabolismo
9.
Can J Physiol Pharmacol ; 99(5): 449-460, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33689451

RESUMO

Ribavirin is a guanosine analog with broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico, and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection, whereas the drug itself did not show any toxic effect over the concentration range tested. In silico analysis suggested that ribavirin has a broad-spectrum impact on SARS-CoV-2, acting at different viral proteins. According to the detailed molecular techniques, ribavirin was shown to decrease the expression of TMPRSS2 at both mRNA and protein levels 48 h after treatment. The suppressive effect of ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that ribavirin also showed an inhibitory effect on the TMPRSS2 enzyme. Based on these results, we hypothesized that ribavirin may inhibit the expression of TMPRSS2 by modulating the formation of inhibitory G-quadruplex structures at the TMPRSS2 promoter. As a conclusion, ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effects of TMPRSS2 and ACE2 expression.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Regulação para Baixo/efeitos dos fármacos , Ribavirina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Animais , Células CACO-2 , Chlorocebus aethiops , Quadruplex G/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas/genética , SARS-CoV-2/fisiologia , Serina Endopeptidases/genética , Células Vero
10.
Viruses ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546185

RESUMO

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG's antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Tapsigargina/farmacologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Coronavirus Humano OC43/fisiologia , Estresse do Retículo Endoplasmático , Humanos , Vírus da Influenza A Subtipo H1N1/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Ribavirina/farmacologia , SARS-CoV-2/fisiologia , Tapsigargina/uso terapêutico , Replicação Viral/efeitos dos fármacos
11.
Toxicol Appl Pharmacol ; 415: 115450, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577917

RESUMO

Eukaryotic translation initiation factor 4E (eIF4E) and protein arginine methyltransferase 5 (PRMT5) are frequently overexpressed in colorectal cancer (CRC) tissues and associated with poor prognosis. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C therapy. The potential of ribavirin to treat CRC remains largely unknown. Ribavirin treatment in CRC cell lines drastically inhibited cell proliferation and colony formation, induced S phase arrest and reduced cyclin D1, cyclin A/E and proliferating cell nuclear antigen (PCNA) levels in vitro, and suppressed tumorigenesis in mouse model of colitis-associated CRC. Mechanistically, ribavirin treatment significantly reduced PRMT5 and eIF4E protein levels and the accumulation of symmetric dimethylation of histone 3 at arginine 8 (H3R8me2s) and that of histone 4 at arginine 3 (H4R3me2s). Importantly, inhibition of PRMT5 by ribavirin resulted in promoted H3R8 methylation in eIF4E promoter region. Our results demonstrate the anti-cancer efficacy of ribavirin in CRC and suggest that the anti-cancer efficacy of ribavirin may be mediated by downregulating PRMT5 levels but not its enzymatic activity.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Metilação de DNA/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Histonas/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Ribavirina/farmacologia , Animais , Neoplasias Associadas a Colite/tratamento farmacológico , Neoplasias Associadas a Colite/enzimologia , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/patologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação para Baixo , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Camundongos Endogâmicos ICR , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/genética , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos
12.
PLoS Comput Biol ; 17(1): e1008535, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33411731

RESUMO

Lassa fever is an haemorrhagic fever caused by Lassa virus (LASV). There is no vaccine approved against LASV and the only recommended antiviral treatment relies on ribavirin, despite limited evidence of efficacy. Recently, the nucleotide analogue favipiravir showed a high antiviral efficacy, with 100% survival obtained in an otherwise fully lethal non-human primate (NHP) model of Lassa fever. However the mechanism of action of the drug is not known and the absence of pharmacokinetic data limits the translation of these results to the human setting. Here we aimed to better understand the antiviral effect of favipiravir by developping the first mathematical model recapitulating Lassa viral dynamics and treatment. We analyzed the viral dynamics in 24 NHPs left untreated or treated with ribavirin or favipiravir, and we put the results in perspective with those obtained with the same drugs in the context of Ebola infection. Our model estimates favipiravir EC50 in vivo to 2.89 µg.mL-1, which is much lower than what was found against Ebola virus. The main mechanism of action of favipiravir was to decrease virus infectivity, with an efficacy of 91% at the highest dose. Based on our knowledge acquired on the drug pharmacokinetics in humans, our model predicts that favipiravir doses larger than 1200 mg twice a day should have the capability to strongly reduce the production infectious virus and provide a milestone towards a future use in humans.


Assuntos
Amidas , Antivirais , Febre Lassa/virologia , Vírus Lassa , Pirazinas , Ribavirina , Amidas/farmacocinética , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/uso terapêutico , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Febre Lassa/tratamento farmacológico , Vírus Lassa/efeitos dos fármacos , Vírus Lassa/patogenicidade , Vírus Lassa/fisiologia , Macaca fascicularis , Modelos Biológicos , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Ribavirina/farmacocinética , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Carga Viral/efeitos dos fármacos
13.
Antiviral Res ; 188: 105016, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33444703

RESUMO

ABMA and its analogue DABMA are two molecules of the adamantane family known to perturbate the endosomal pathway and to inhibit cell infection of several RNA and DNA viruses. Their activity against Rabies Virus (RABV) infection has already been demonstrated in vitro. (Wu et al., 2017, 2019). Here, we describe in more details their mechanism of action by comparison to Arbidol (umifenovir) and Ribavirin, two broad spectrum antivirals against emerging viruses such as Lassa, Ebola, influenza and Hantaan viruses. ABMA and DABMA, delivered 2 h pre-infection, inhibit RABV infection in vitro with an EC50 of 7.8 µM and 14 µM, respectively. They act at post-entry, by causing RABV accumulation within the endosomal compartment and DABMA specifically diminishes the expression of the GTPase Rab7a controlling the fusion of early endosomes to late endosomes or lysosomes. This may suggest that ABMA and DABMA act at different stages of the late endosomal pathway as supported by their different profile of synergy/antagonism with the fusion inhibitor Arbidol. This difference is further confirmed by the RABV mutants induced by successive passages under increasing selective pressure showing a particular involvement of the viral G protein in the DABMA inhibition while ABMA inhibition induces less mutations dispersed in the M, G and L viral proteins. These results suggest new therapeutic perspectives against rabies.


Assuntos
Adamantano/farmacologia , Antivirais/farmacologia , Benzilaminas/farmacologia , Vírus da Raiva/efeitos dos fármacos , Animais , Linhagem Celular , Farmacorresistência Viral , Sinergismo Farmacológico , Endossomos/metabolismo , Indóis/farmacologia , Mutação , Vírus da Raiva/genética , Vírus da Raiva/fisiologia , Ribavirina/farmacologia , Proteínas Virais/genética , Internalização do Vírus/efeitos dos fármacos
14.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33440983

RESUMO

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Assuntos
Antivirais/uso terapêutico , COVID-19/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Combinação de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/farmacologia , Indóis/uso terapêutico , Interferons/farmacologia , Interferons/uso terapêutico , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
15.
EMBO Mol Med ; 13(1): e13105, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33015938

RESUMO

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/farmacologia , Reposicionamento de Medicamentos/métodos , Ésteres/farmacologia , Ésteres/uso terapêutico , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Jpn J Infect Dis ; 74(2): 154-156, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32863356

RESUMO

Subacute sclerosing panencephalitis (SSPE) is a late-onset, intractable, and fatal viral disease caused by persistent infection of the central nervous system with a measles virus mutant (SSPE virus). In Japan, interferon-α and ribavirin are administered intracerebroventricularly to patients with SSPE. However, as the therapeutic effect is insufficient, more effective drugs are needed. Favipiravir, which is clinically used as an anti-influenza drug, demonstrates anti-viral effects against RNA viruses. In this study, the antiviral effect of favipiravir against measles virus (Edmonston strain) and SSPE virus (Yamagata-1 strain) was examined in vitro. The 50% effective concentration (EC50) of favipiravir (inhibiting viral plaque formation by 50%) against Edmonston and Yamagata-1 strains were 108.7 ± 2.0 µM (17.1 ± 0.3 µg/mL) and 38.6 ± 6.0 µM (6.1 ± 0.9 µg/mL), respectively, which were similar to those of ribavirin. The antiviral activity of favipiravir against the SSPE virus was demonstrated for the first time in this study.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Sarampo/tratamento farmacológico , Pirazinas/farmacologia , Panencefalite Esclerosante Subaguda/tratamento farmacológico , Animais , Chlorocebus aethiops , Humanos , Interferon-alfa/farmacologia , Japão , Sarampo/patologia , Vírus do Sarampo/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ribavirina/farmacologia , Vírus SSPE/efeitos dos fármacos , Panencefalite Esclerosante Subaguda/patologia , Células Vero
17.
Biochem Biophys Res Commun ; 534: 740-746, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33250174

RESUMO

Recombinant viruses expressing fluorescent or luminescent reporter proteins are used to quantitate and visualize viral replication and transmission. Here, we used a split NanoLuc luciferase (NLuc) system comprising large LgBiT and small HiBiT peptide fragments to generate stable reporter rotaviruses (RVs). Reporter RVs expressing NSP1-HiBiT fusion protein were generated by placing an 11 amino acid HiBiT peptide tag at the C-terminus of the intact simian RV NSP1 open reading frame or truncated human RV NSP1 open reading frame. Virus-infected cell lysates exhibited NLuc activity that paralleled virus replication. The antiviral activity of neutralizing antibodies and antiviral reagents against the recombinant HiBiT reporter viruses were monitored by measuring reductions in NLuc expression. These findings demonstrate that the HiBiT reporter RV systems are powerful tools for studying the viral life cycle and pathogenesis, and a robust platform for developing novel antiviral drugs.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Genes Reporter , Luciferases/genética , Peptídeos/genética , Rotavirus/genética , Animais , Antivirais/farmacologia , Cricetinae , Humanos , Camundongos , Microrganismos Geneticamente Modificados , Testes de Neutralização , Ribavirina/farmacologia , Rotavirus/fisiologia , Infecções por Rotavirus/tratamento farmacológico , Infecções por Rotavirus/virologia , Proteínas não Estruturais Virais/genética , Replicação Viral/genética
18.
Expert Rev Anti Infect Ther ; 19(8): 1053-1059, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33307880

RESUMO

OBJECTIVES: Extent of post-treatment fibrosis change in patients with different stages of fibrosis not fully known. We aimed to study changes in liver fibrosis in chronic hepatitis C patients who were treated with pegylated interferon/ribavirin (PEG/RBV) or direct acting antivirals (DAAs). METHODS: Retrospective evaluation of results of transient elastography (TE) was done before and 1 year after end of treatment for patients treated with PEG/RBV (n = 268) and DAAs (n = 245). RESULTS: The average age was 45.54 ± 10.64 years; mainly males. All patients in the DAAs group achieved sustained virological response (SVR), unlike 56.3% of the patients in the PEG/RBV group. F3-F4 fibrosis was predominant in the PEG/RBV nonresponder patients (51.3%) and DAAs responders (57.1%). TE decreased 1 year after end of treatment (p = 0.001) in the viral responders of the PEG/RBV group (7.44 ± 4.02 vs. 10.24 ± 7.29 kPa) and DAAs group (12.12 ± 9.21 vs. 16.81 ± 12.84 kPa) respectively. The delta TE change in the DAAs responders was higher than the PEG/RBV responders (p = 0.001) and PEG/RBV nonresponders (p = 0.001). The percentage of patients with liver fibrosis regression was higher in DAAs responders (52.5%) than in PEG/RBV responders (23.3%). CONCLUSION: Treatment with DAAs is associated with fibrosis improvement more than treatment with PEG/RBV in chronic hepatitis C patients.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Adulto , Antivirais/farmacologia , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Interferons/administração & dosagem , Interferons/farmacologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/química , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/farmacologia
19.
J Ethnopharmacol ; 266: 113401, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32980486

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the main pathogenesis of severe hand, foot and mouth disease (HFMD) is that the heat and wet poisons are deeply trapped in the viscera, which causes the deficiency of Qi and Yin in the patient's body. Ginsenoside Rb1 (Rb1) is the most abundant triterpenoid saponin in Panax quinquefolius L., which has the function of Qi-invigorating and Yin-nourishing. Enterovirus 71 (EV71) is one of the causative pathogens of HFMD, especially the form associated with some lethal complications. Therefore, the therapeutic effect of Rb1 on this disease caused by EV71 infection is worth exploring. AIM OF THE STUDY: We explored the effective antiviral activities of Rb1 against EV71 in vitro and in vivo and investigated its preliminary antiviral mechanisms. MATERIAL AND METHODS: EV71-infected two-day-old suckling mice model was employed to detect the antiviral effects of Rb1 in vivo. To detect the antiviral effects of Rb1 in vitro, cytopathic effect (CPE) reduction assay was performed in EV71-infected Rhabdomyosarcoma (RD) cells. Interferon (IFN)-ß interference experiment was employed to detect the antiviral mechanism of Rb1. RESULTS: In this paper, we first found that Rb1 exhibited strong antiviral activities in EV71-infected suckling mice when compared to those of ribavirin. Administration of Rb1 reduced the CPE of EV71-infected RD cells in a dose-dependent manner. Moreover, EV71-induced viral protein-1 (VP-1) expression was significantly reduced by Rb1 administration in vitro and in vivo. Furthermore, Rb1 treatment could induce high cellular and humoral immune responses in vivo. Meanwhile, Rb1 contributed to the enhanced Type I IFN responses and IFN-ß knockdown reversed the antiviral activity of Rb1 in vitro. CONCLUSION: In summary, our findings suggest that Rb1 is an immune-stimulatory agent and provide an insight into therapeutic potentials of Rb1 for the treatment of EV71 infection.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Ginsenosídeos/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Antivirais/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infecções por Enterovirus/virologia , Ginsenosídeos/administração & dosagem , Humanos , Camundongos , Camundongos Endogâmicos ICR , Panax/química , Rabdomiossarcoma/virologia , Ribavirina/farmacologia
20.
Cells ; 10(1)2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374379

RESUMO

Musculoskeletal injuries represent a challenging medical problem. Although the skeletal muscle is able to regenerate and recover after injury, the process engaged with conservative therapy can be inefficient, leading to a high re-injury rate. In addition, the formation of scar tissue implies an alteration of mechanical properties in muscle. There is still a need for new treatments of the injured muscle. NeuroHeal may be one option. Published studies demonstrated that it reduces muscle atrophy due to denervation and disuse. The main objective of the present work was to assess the potential of NeuroHeal to improve muscle regeneration after traumatic injury. Secondary objectives included characterizing the effect of NeuroHeal treatment on satellite cell biology. We used a rat model of sport-induced injury in the gastrocnemius and analyzed the effects of NeuroHeal on functional recovery by means of electrophysiology and tetanic force analysis. These studies were accompanied by immunohistochemistry of the injured muscle to analyze fibrosis, satellite cell state, and fiber type. In addition, we used an in vitro model to determine the effect of NeuroHeal on myoblast biology and partially decipher its mechanism of action. The results showed that NeuroHeal treatment advanced muscle fiber recovery after injury in a preclinical model of muscle injury, and significantly reduced the formation of scar tissue. In vitro, we observed that NeuroHeal accelerated the formation of myotubes. The results pave the way for novel therapeutic avenues for muscle/tendinous disorders.


Assuntos
Acamprosato , Traumatismos em Atletas/tratamento farmacológico , Músculo Esquelético , Fármacos Neuroprotetores , Recuperação de Função Fisiológica/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Ribavirina , Acamprosato/administração & dosagem , Acamprosato/farmacologia , Animais , Linhagem Celular , Combinação de Medicamentos , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Mioblastos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Ribavirina/administração & dosagem , Ribavirina/farmacologia
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