Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.132
Filtrar
1.
PLoS One ; 15(12): e0244762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378413

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and is characterized by the accumulation of fat in the liver (steatosis). NAFLD can transition into non-alcoholic steatohepatitis (NASH), with liver cell injury, inflammation, and an increased risk of fibrosis. We previously found that injections of either 1866, a synthetic ligand for the lectin receptor CD209, or DANA, a sialidase inhibitor, can inhibit inflammation and fibrosis in multiple animal models. The methionine and choline-deficient (MCD) diet is a model of NASH which results in the rapid induction of liver steatosis and inflammation. In this report, we show that for C57BL/6 mice on a MCD diet, injections of both 1866 and DANA reversed MCD diet-induced decreases in white fat, decreases in adipocyte size, and white fat inflammation. However, these effects were not observed in type 2 diabetic db/db mice on a MCD diet. In db/db mice on a MCD diet, 1866 decreased liver steatosis, but these effects were not observed in C57BL/6 mice. There was no correlation between the ability of 1866 or DANA to affect steatosis and the effects of these compounds on the density of liver macrophage cells expressing CLEC4F, CD64, F4/80, or Mac2. Together these results indicate that 1866 and DANA modulate adipocyte size and adipose tissue macrophage populations, that 1866 could be useful for modulating steatosis, and that changes in the local density of 4 different liver macrophages cell types do not correlate with effects on liver steatosis.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Moléculas de Adesão Celular/agonistas , Lectinas Tipo C/agonistas , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ácido N-Acetilneuramínico/análogos & derivados , Neuraminidase/antagonistas & inibidores , Receptores de Superfície Celular/agonistas , Tecido Adiposo/metabolismo , Animais , Deficiência de Colina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Ácido N-Acetilneuramínico/farmacologia , Ácido N-Acetilneuramínico/uso terapêutico , Neuraminidase/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
2.
Nat Commun ; 11(1): 5597, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154358

RESUMO

Seasonal influenza epidemics lead to 3-5 million severe infections and 290,000-650,000 annual global deaths. With deaths from the 1918 influenza pandemic estimated at >50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD50 virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.


Assuntos
Antivirais/administração & dosagem , Antivirais/farmacologia , Imunoterapia/métodos , Infecções por Orthomyxoviridae/tratamento farmacológico , 2,4-Dinitrofenol/administração & dosagem , 2,4-Dinitrofenol/química , 2,4-Dinitrofenol/imunologia , Administração Intranasal , Animais , Anticorpos/administração & dosagem , Anticorpos/imunologia , Antivirais/química , Linhagem Celular , Citotoxicidade Imunológica/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/enzimologia , Vírus da Influenza B/fisiologia , Infusões Parenterais , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Ligação Proteica , Resultado do Tratamento , Liberação de Vírus/efeitos dos fármacos , Zanamivir/administração & dosagem , Zanamivir/química , Zanamivir/farmacologia
3.
SAR QSAR Environ Res ; 31(11): 803-814, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32938208

RESUMO

High-dimensionality is one of the major problems which affect the quality of the quantitative structure-activity relationship (QSAR) modelling. Obtaining a reliable QSAR model with few descriptors is an essential procedure in chemometrics. The binary grasshopper optimization algorithm (BGOA) is a new meta-heuristic optimization algorithm, which has been used successfully to perform feature selection. In this paper, four new transfer functions were adapted to improve the exploration and exploitation capability of the BGOA in QSAR modelling of influenza A viruses (H1N1). The QSAR model with these new quadratic transfer functions was internally and externally validated based on MSEtrain, Y-randomization test, MSEtest, and the applicability domain (AD). The validation results indicate that the model is robust and not due to chance correlation. In addition, the results indicate that the descriptor selection and prediction performance of the QSAR model for training dataset outperform the other S-shaped and V-shaped transfer functions. QSAR model using quadratic transfer function shows the lowest MSEtrain. For the test dataset, proposed QSAR model shows lower value of MSEtest compared with the other methods, indicating its higher predictive ability. In conclusion, the results reveal that the proposed QSAR model is an efficient approach for modelling high-dimensional QSAR models and it is useful for the estimation of IC50 values of neuraminidase inhibitors that have not been experimentally tested.


Assuntos
Algoritmos , Antivirais/farmacologia , Inibidores Enzimáticos/química , Vírus da Influenza A Subtipo H1N1/enzimologia , Neuraminidase/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Proteínas Virais/antagonistas & inibidores , Animais , Biologia Computacional , Desenho de Fármacos , Gafanhotos , Modelos Químicos
4.
BMC Infect Dis ; 20(1): 628, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842994

RESUMO

BACKGROUND: Guidelines emphasize prompt antiviral treatment in severe influenza patients. Although nearly a 50% of severe influenza present with pneumonia, the effect of early (≤ 2 days after illness onset) neuraminidase inhibitor (NAI) use on the clinical outcomes of influenza A-related pneumonia (FluA-p) has rarely been assessed. Furthermore, data about the administration of NAIs in the real-world management of Flu-p in China are limited. METHODS: Data of patients hospitalised with FluA-p from five teaching hospitals in China from 1 January 2013 to 31 December 2018 were reviewed retrospectively. The impact of early NAI therapy on the outcomes in FluA-p patients, and the indications of early NAI administration by clinicians were evaluated by logistic regression analysis. RESULTS: In total, 693 FluA-p patients were included. Of these patients, 33.5% (232/693) were treated early. After adjusting for weighted propensity scores for treatment, systemic corticosteroid and antibiotic use, a multivariate logistic regression model showed that early NAI therapy was associated with decreased risk for invasive ventilation [odds ratio (OR) 0.511, 95% confidence interval (CI) 0.312-0.835, p = 0.007) and 30-day mortality (OR 0.533, 95% CI 0.210-0.807, p < 0.001) in FluA-p patients. A multivariate logistic regression model confirmed early NAI use (OR 0.415, 95% CI 0.195-0.858, p = 0.001) was a predictor for 30-day mortality in FluA-p patients and a positive rapid influenza diagnostic test was the only indication (OR 3.586, 95% CI 1.259-10.219, p < 0.001) related to the prescription of early NAI by clinicians. CONCLUSIONS: Early NAI therapy is associated with better outcomes in FluA-p patients. Improved education and training of clinicians on the guidelines of influenza are needed.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Neuraminidase/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Prevenção Secundária , Adulto , Idoso , China/epidemiologia , Feminino , Hospitalização , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , RNA Viral/genética , Estudos Retrospectivos , Resultado do Tratamento
5.
J Chem Inf Model ; 60(10): 4582-4593, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-32845150

RESUMO

Artificial intelligence and multiobjective optimization represent promising solutions to bridge chemical and biological landscapes by addressing the automated de novo design of compounds as a result of a humanlike creative process. In the present study, we conceived a novel pair-based multiobjective approach implemented in an adapted SMILES generative algorithm based on recurrent neural networks for the automated de novo design of new molecules whose overall features are optimized by finding the best trade-offs among relevant physicochemical properties (MW, logP, HBA, HBD) and additional similarity-based constraints biasing specific biological targets. In this respect, we carried out the de novo design of chemical libraries targeting neuraminidase, acetylcholinesterase, and the main protease of severe acute respiratory syndrome coronavirus 2. Several quality metrics were employed to assess drug-likeness, chemical feasibility, diversity content, and validity. Molecular docking was finally carried out to better evaluate the scoring and posing of the de novo generated molecules with respect to X-ray cognate ligands of the corresponding molecular counterparts. Our results indicate that artificial intelligence and multiobjective optimization allow us to capture the latent links joining chemical and biological aspects, thus providing easy-to-use options for customizable design strategies, which are especially effective for both lead generation and lead optimization. The algorithm is freely downloadable at https://github.com/alberdom88/moo-denovo and all of the data are available as Supporting Information.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Redes Neurais de Computação , Acetilcolinesterase/metabolismo , Antivirais/química , Antivirais/farmacologia , Inteligência Artificial , Betacoronavirus/enzimologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/metabolismo , Humanos , Vírus da Influenza A/enzimologia , Simulação de Acoplamento Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
6.
BMC Infect Dis ; 20(1): 478, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631240

RESUMO

BACKGROUND: Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir. CASE PRESENTATION: A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/µL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2. CONCLUSIONS: In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.


Assuntos
Antivirais/uso terapêutico , Ciclopentanos/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Ácidos Carbocíclicos , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacologia , Dibenzotiepinas , Farmacorresistência Viral/genética , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Guanidinas/efeitos adversos , Guanidinas/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hospedeiro Imunocomprometido , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Morfolinas , Mutação , Neuraminidase/antagonistas & inibidores , Neuraminidase/genética , Oseltamivir/uso terapêutico , Piridonas , Transplante Homólogo/métodos , Resultado do Tratamento , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética
7.
Intern Med ; 59(12): 1509-1513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32536677

RESUMO

Objective Baloxavir marboxil is a novel anti-influenza drug reported to have an early antiviral effect, although it also causes the appearance of variant viruses with a reduced susceptibility to baloxavir. In Japan, four neuraminidase inhibitors (NAIs) have been commonly used to treat patients with influenza. In clinical practice, the differences in the effects of baloxavir and NAIs have not been sufficiently examined. Our objective was to clarify the clinical differences in efficacy between baloxavir and NAIs. Methods A multicenter, observational study was conducted using postcard questionnaires during the 2018-19 influenza season. Patients who were prescribed anti-influenza drugs were provided postcard questionnaires asking about their background characteristics and their body temperatures. The factors associated with the early alleviation of the fever were analyzed, and the duration of the fever was compared between the baloxavir group and the NAI group. Results A total of 295 patients with influenza A, ranging in age from 0-91 years old, were enrolled in this study. A multivariate analysis showed that treatment with baloxavir and a duration from the onset to the start of treatment ≥2.5 days were factors contributing to the early alleviation of the fever from the start of treatment. The duration of the fever was significantly shorter in the baloxavir group than in the NAI group (p=0.002). Conclusion The present survey showed that baloxavir was significantly more effective than NAIs for treating patients with influenza A in clinical practice.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Dibenzotiepinas , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Morfolinas , Análise Multivariada , Piridonas , Resultado do Tratamento , Adulto Jovem
8.
Exp Parasitol ; 216: 107943, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32598890

RESUMO

The search for novel therapeutic candidates against animal trypanosomiasis is an ongoing scientific endevour because of the negative impacts of the disease to the African livestock industry. In this study, the in vivo therapeutic potentials of phytol toward Trypanosoma congolense infection and the inhibitory effects on trypanosomal sialidase were investigated. Rats were infected with T. congolense and administered daily oral treatment of 50 and 100 mg/kg BW of phytol. Within the first 10 days of the treatment, no antitrypanosomal activity was recorded but a moderate trypanostatic activity was observed from day 17-day 21 pi. However, at 100 mg/kg BW, phytol demonstrated a significant (p < 0.05) ameliorative potentials toward T. congolense-induced host-associated pathological damages such as anaemia, hepatic and renal damages; and the data was comparable to diminazine aceturate. Moreover, the T. congolense caused a significant (p < 0.05) increase in free serum sialic acid level which was significantly (p < 0.05) prevented in the presence of phytol (100 mg/kg BW). In an in vitro analysis, phytol inhibited partially purified T. congolense sialidase using an uncompetitive inhibition pattern with inhibition binding constant of 261.24 µmol/mL. Subsequently, molecular docking revealed that the compound binds to homology modelled trypanosomal sialidase with a binding free energy of -6.7 kcal/mol which was mediated via a single hydrogen bond while Trp324 and Pro274 were the critical binding residues. We concluded that phytol has moderate trypanostatic activity but with a great potential in mitigating the host-associated cellular damages while the anaemia amelioration was mediated, in part, through the inhibition of sialidase.


Assuntos
Antiprotozoários/uso terapêutico , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Fitol/uso terapêutico , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/veterinária , Animais , Antiprotozoários/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gado , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/veterinária , Neuraminidase/química , Neuraminidase/isolamento & purificação , Fitol/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/tratamento farmacológico
9.
In Vivo ; 34(3 Suppl): 1597-1602, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503817

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Cloroquina/análogos & derivados , Cloroquina/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/veterinária , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Drogas em Investigação/uso terapêutico , Humanos , Indóis/uso terapêutico , Lopinavir/uso terapêutico , Estudos Multicêntricos como Assunto , Neuraminidase/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Primatas , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Resultado do Tratamento
10.
PLoS One ; 15(5): e0233001, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401814

RESUMO

Antibodies against influenza virus neuraminidase (NA) protein prevent releasing of the virus from host cells and spreading of infection foci and are considered the 'second line of defence' against influenza. Haemagglutinin inhibition antibody-low responders (HI-LRs) are present among influenza split vaccine recipients. The NA inhibition (NAI) antibody response in vaccinees is worth exploring, especially those in the HI-LRs population. We collected pre- and post-vaccination sera from 61 recipients of an inactivated, monovalent, split vaccine against A/H1N1pdm09 and acute and convalescent sera from 49 unvaccinated patients naturally infected with the A/H1N1pdm09 virus during the 2009 influenza pandemic. All samples were subjected to haemagglutinin inhibition (HI), NAI and neutralisation assays. Most paired sera from naturally infected patients exhibited marked elevation in the NAI activity, and seroconversion rates (SCR) among HI-LRs and HI-responders (HI-Rs) were 60% and 87%, respectively; however, those from vaccinees displayed low increase in the NAI activity, and the SCR among HI-LRs and HI-Rs were 0% and 12%, respectively. In both HI-LRs and HI-Rs, vaccination with the inactivated, monovalent, split vaccine failed to elicit the NAI activity efficiently in the sera of the naive population, compared with the natural infection. Hence, the improvement of influenza vaccines is warranted to elicit not only HI but also NAI antibodies.


Assuntos
Anticorpos Antivirais/sangue , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Neuraminidase/antagonistas & inibidores , Neuraminidase/imunologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Criança , Pré-Escolar , Feminino , História do Século XXI , Humanos , Influenza Humana/epidemiologia , Japão , Masculino , Pessoa de Meia-Idade , Pandemias/história , Vacinas de Produtos Inativados/imunologia , Adulto Jovem
12.
PLoS Pathog ; 16(4): e1008395, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32294137

RESUMO

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/tratamento farmacológico , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Replicação Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos , Animais , Dibenzotiepinas , Feminino , Furões , Morfolinas , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia , Piridonas
13.
J Infect Chemother ; 26(8): 775-779, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32249161

RESUMO

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the epidemic viruses in the 2018-19 Japanese influenza season, we measured the 50% inhibitory concentration (IC50) of four NAIs, oseltamivir, zanamivir, peramivir, and laninamivir, for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2017-18 seasons. Viral isolation was done with specimens obtained prior to and after treatment, and the type/subtype was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Virus isolates, 51 A(H1N1)pdm09, 125 A(H3N2), and one B, were measured in the 2018-19 season and the geometric mean IC50s of the four NAIs were quite comparable to the previous eight studied seasons. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2018-19 season prior to drug administration, although such A(H1N1)pdm09 were found in two, two, and two samples in the 2010-11, 2013-14, and 2015-16 seasons, respectively. No isolates with highly reduced sensitivity to the four NAIs were found for A(H3N2) or B through the 2010-11 to 2018-19 seasons. Among 18 samples with A(H1N1)pdm09 virus isolated after NAI administration, highly reduced sensitivity to oseltamivir and peramivir was detected from one of the five patients treated with oseltamivir. These results suggest that the sensitivity to the four commonly used NAIs has been maintained, although viruses with highly reduced sensitivity to oseltamivir and peramivir have emerged in some adult patients treated with oseltamivir.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/virologia , Neuraminidase/antagonistas & inibidores , Ácidos Carbocíclicos , Adolescente , Adulto , Criança , Ciclopentanos/farmacologia , Farmacorresistência Viral , Feminino , Guanidinas/farmacologia , Humanos , Influenza Humana/tratamento farmacológico , Concentração Inibidora 50 , Japão , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Oseltamivir/farmacologia , Piranos , Estações do Ano , Ácidos Siálicos , Adulto Jovem , Zanamivir/análogos & derivados , Zanamivir/farmacologia
14.
Sci Rep ; 10(1): 5198, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251344

RESUMO

Sialidase cleaves sialic acid residues from a sialoglycoconjugate: oligosaccharides, glycolipids and glycoproteins that contain sialic acid. Histochemical imaging of the mouse pancreas using a benzothiazolylphenol-based sialic acid derivative (BTP3-Neu5Ac), a highly sensitive histochemical imaging probe used to assess sialidase activity, showed that pancreatic islets have intense sialidase activity. The sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) remarkably enhances glutamate release from hippocampal neurons. Since there are many similar processes between synaptic vesicle exocytosis and secretory granule exocytosis, we investigated the effect of DANA on insulin release from ß-cells. Insulin release was induced in INS-1D cells by treatment with 8.3 mM glucose, and the release was enhanced by treatment with DANA. In a mouse intraperitoneal glucose tolerance test, the increase in serum insulin levels was enhanced by intravenous injection with DANA. However, under fasting conditions, insulin release was not enhanced by treatment with DANA. Calcium oscillations induced by 8.3 mM glucose treatment of INS-1D cells were not affected by DANA. Blood insulin levels in sialidase isozyme Neu3-deficient mice were significantly higher than those in WT mice under ad libitum feeding conditions, but the levels were not different under fasting conditions. These results indicate that DANA is a glucose-dependent potentiator of insulin secretion. The sialidase inhibitor may be useful for anti-diabetic treatment with a low risk of hypoglycemia.


Assuntos
Glucose/fisiologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ácido N-Acetilneuramínico/análogos & derivados , Neuraminidase/antagonistas & inibidores , Animais , Sinalização do Cálcio/efeitos dos fármacos , Corantes/análise , Avaliação Pré-Clínica de Medicamentos , Jejum/sangue , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Injeções Intravenosas , Insulina/sangue , Secreção de Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/farmacologia , Neuraminidase/fisiologia
15.
Public Health Res Pract ; 30(1)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32152617

RESUMO

BACKGROUND: Influenza attack rates in closed population settings, such as residential aged care facilities (RACFs), can be more than 50% during annual epidemics. Uncertainty about the effectiveness of neuraminidase inhibitors (NAIs) as prophylaxis for influenza outbreaks has led to variations in their use in RACFs in New South Wales (NSW), Australia. OBJECTIVES: To examine the use of prophylactic NAIs by NSW RACFs for residents during influenza outbreaks in the 2015 influenza season. METHODS: A prospective cohort study of influenza outbreaks reported to NSW Public Health Units from 1 June 2015 - 31 October 2015. RESULTS: Eighty-eight RACFs reported influenza outbreaks; 86 were included in the study. Fifty-two RACFs used prophylactic NAIs; 34 did not. The median time to start NAI prophylaxis from the onset date of the first case was 8.5 days (range 2-23). The average proportion of residents within a facility that received prophylaxis was 51%percnt; (range 0.7-95). CONCLUSION: Variations in the use of prophylactic NAIs exist across RACFs. Earlier initiation of NAI prophylaxis, improved resident coverage where appropriate and other practice changes are recommended for the management of influenza outbreaks in RACFs.


Assuntos
Surtos de Doenças/prevenção & controle , Inibidores Enzimáticos , Influenza Humana/prevenção & controle , Neuraminidase , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Vírus da Influenza A , Vírus da Influenza B , Masculino , Neuraminidase/antagonistas & inibidores , New South Wales , Estudos Prospectivos
16.
Transl Res ; 220: 33-42, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088166

RESUMO

Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.


Assuntos
Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Amidas/uso terapêutico , Anticorpos Neutralizantes/sangue , Citidina/análogos & derivados , Dibenzotiepinas , Farmacorresistência Viral , Humanos , Hidroxilaminas , Morfolinas , Neuraminidase/antagonistas & inibidores , Oxazinas/uso terapêutico , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Piridonas , Ribonucleosídeos/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Replicação Viral/efeitos dos fármacos
17.
Eur J Med Chem ; 191: 112147, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092589

RESUMO

From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH2 position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH2 position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Galinhas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Vírus da Influenza A/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade
18.
Molecules ; 25(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070030

RESUMO

The neuraminidase enzyme (NA) from the influenza virus is responsible for the proliferation and infections of the virus progeny, prompting several efforts to discover and optimize effective neuraminidase inhibitors. The main aim of this study is to discover a new potential neuraminidase inhibitor that comes from Garcinia celebica leaves (GCL). The bioassay-guided isolation method was performed to obtain lead compounds. The binding interaction of the isolated compounds was predicted by using molecular docking studies. Friedeline (GC1, logP > 5.0), two lanastone derivatives (methyl-3α,23-dihydroxy-17,14-friedolanstan-8,14,24-trien-26-oat (GC2) and 24E-3a,9,23-trihydroxy-17,14-friedolanostan-14,24-dien-26-oate (GC3) with LogP > 5.0) and catechin (GC4, LogP = 1.4) were identified. The inhibitory potency of these four compounds on NA from C. perfringens and H1N1 was found to be as follows: GC4 > GC2 > GC3 > GC1. All compounds exhibited higher inhibitory activity towards C. perfringens NA compared to H1N1 NA. From the molecular docking results, GC4 favorably docked and interacted with Arg118, Arg371, Arg292, Glu276 and Trp178 residues, whilst GC2 interacted with Arg118, Arg371, Arg292, Ile222, Arg224 and Ser246. GC3 interacted with Tyr406 only. GC4 had potent NA inhibition with free energy of binding of -12 kcal/mol. In the enzyme inhibition study, GC4 showed the highest activity with an IC50 of 60.3 µM and 91.0 µM for C. perfringens NA and H1N1 NA-respectively.


Assuntos
Antivirais/química , Antivirais/isolamento & purificação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Garcinia/química , Neuraminidase/antagonistas & inibidores , Folhas de Planta/química , Simulação de Acoplamento Molecular , Estrutura Molecular
19.
Int J Mol Sci ; 21(3)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028720

RESUMO

Streptococcus pneumoniae can cause diseases such as pneumonia. Broad-spectrum antibiotic therapy for Streptococcus pneumoniae is increasingly limited due to the emergence of drug-resistant strains. The development of novel drugs is still currently of focus. Abundant polyphenols have been demonstrated to have antivirus and antibacterial ability. Chlorogenic acid is one of the representatives that has been proven to have the potential to inhibit both the influenza virus and Streptococcus pneumoniae. However, for such a potential neuraminidase inhibitor, the interaction mechanism studies between chlorogenic acid and Streptococcus pneumoniae neuraminidase are rare. In the current study, the binding mechanism of chlorogenic acid and Streptococcus pneumoniae neuraminidase were investigated by molecular simulation. The results indicated that chlorogenic acid might establish the interaction with Streptococcus pneumoniae neuraminidase via hydrogen bonds, salt bridge, and cation-π. The vital residues involved Arg347, Ile348, Lys440, Asp372, Asp417, and Glu768. The side chain of Arg347 might form a cap-like structure to lock the chlorogenic acid to the active site. The results from binding energy calculation indicated that chlorogenic acid had strong binding potential with neuraminidase. The results predicted a detailed binding mechanism of a potential Streptococcus pneumoniae neuraminidase inhibitor, which will be provide a theoretical basis for the mechanism of new inhibitors.


Assuntos
Antibacterianos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Ácido Clorogênico/metabolismo , Inibidores Enzimáticos/metabolismo , Magnoliopsida/química , Neuraminidase/antagonistas & inibidores , Streptococcus pneumoniae/enzimologia , Sítios de Ligação , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
20.
Sci Rep ; 10(1): 2161, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034220

RESUMO

While molecular-targeted drugs have demonstrated strong therapeutic efficacy against diverse diseases such as cancer and infection, the appearance of drug resistance associated with genetic variations in individual patients or pathogens has severely limited their clinical efficacy. Therefore, precision medicine approaches based on the personal genomic background provide promising strategies to enhance the effectiveness of molecular-targeted therapies. However, identifying drug resistance mutations in individuals by combining DNA sequencing and in vitro analyses is generally time consuming and costly. In contrast, in silico computation of protein-drug binding free energies allows for the rapid prediction of drug sensitivity changes associated with specific genetic mutations. Although conventional alchemical free energy computation methods have been used to quantify mutation-induced drug sensitivity changes in some protein targets, these methods are often adversely affected by free energy convergence. In this paper, we demonstrate significant improvements in prediction performance and free energy convergence by employing an alchemical mutation protocol, MutationFEP, which directly estimates binding free energy differences associated with protein mutations in three types of a protein and drug system. The superior performance of MutationFEP appears to be attributable to its more-moderate perturbation scheme. Therefore, this study provides a deeper level of insight into computer-assisted precision medicine.


Assuntos
Resistência a Medicamentos , Simulação de Acoplamento Molecular/métodos , Mutação , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/química , Aldeído Redutase/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/química , Quinase do Linfoma Anaplásico/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular/normas , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Neuraminidase/genética , Sensibilidade e Especificidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...