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1.
Artigo em Inglês | MEDLINE | ID: mdl-32178606

RESUMO

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 3993 human influenza-positive samples during 2018. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or hens' eggs for use as potential seasonal influenza vaccine virus candidates. In 2018, influenza A(H1)pdm09 viruses predominated over influenza A(H3) and B viruses, accounting for a total of 53% of all viruses analysed. The majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO-recommended vaccine strains for the Southern Hemisphere in 2018. However, phylogenetic analysis indicated that a significant proportion of circulating A(H3) viruses had undergone genetic drift relative to the WHO-recommended vaccine strain for 2018. Of 2864 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, three A(H1)pdm09 viruses showed highly reduced inhibition by oseltamivir, while one B/Victoria virus showed highly reduced inhibition by both oseltamivir and zanamivir.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A , Vírus da Influenza B , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Animais , Antígenos Virais , Austrália/epidemiologia , Galinhas , Farmacorresistência Viral , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/genética , Vacinas contra Influenza/uso terapêutico , Oseltamivir , Filogenia , Organização Mundial da Saúde , Zanamivir
3.
Food Chem Toxicol ; 135: 110985, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765700

RESUMO

Investigation of antiviral and cytotoxic effect of quercetin 3-glucoside (Q3G) from Dianthus superbus L over influenza virus infection and replication were studied. Moreover, anti-influenza mechanism was screened by time-dependent antiviral assay, virus-induced symptoms and related gene expressions. The blockade of cap-binding domain of polymerase basic protein subunit were analysed by molecular docking study. The Q3G demonstrated potent antiviral activity showing 4.93, 6.43, 9.94, 8.3, and 7.1 µg/mL of IC50 for A/PR/8/34, A/Victoria/3/75, A/WS/33, B/Maryland/1/59, and B/Lee/40, respectively. The cellular toxicity of Q3G and oseltamivir (control) were tested and >100 µg/mL of CC50 value considered as nontoxic. Influenza A virus infection induced a higher ROS production, however potentially reduced by Q3G treatment and significantly blocked virus infection induced acidic vesicular organelles (AVO). Moreover, Q3G has no inhibitory effect for neuraminidase activity but blocked virus replication through time dependent assay and showed more competitive binding affinity (-8.0 kcal/mal) than GTP (-7.0 kcal/mol) to block polymerase basic protein-2 subunit of influenza virus. Q3G from D. superbus showed potent antiviral activity against influenza A and B viruses with suppressive effect on virus-induced cellular ROS generation and AVO formation. Thus, this study provided a new line of research for Q3G to develop possible natural anti-influenza drug.


Assuntos
Antivirais/farmacologia , Dianthus/química , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Antivirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Cães , Humanos , Técnicas In Vitro , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Vírus da Influenza B/genética , Vírus da Influenza B/fisiologia , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Quercetina/farmacologia , Quercetina/toxicidade , RNA Viral/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Replicação Viral/efeitos dos fármacos
4.
Curr Top Med Chem ; 20(2): 132-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31880262

RESUMO

BACKGROUND: Since the influenza virus is the main cause of acute seasonal respiratory infections and pandemic outbreaks, antiviral drugs are critical to mitigate infections and impair chain of transmission. Neuraminidase inhibitors (NAIs) are the main class of anti-influenza drugs in clinical use. Nevertheless, resistance to oseltamivir (OST), the most used NAI, has been detected in circulating strains of the influenza virus. Therefore, novel compounds with anti-influenza activity are necessary. OBJECTIVE: To verify whether the NA from influenza A and B virus is susceptible to the compound 4-(4- phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo). METHODS: Cell-free neuraminidase inhibition assays were performed with Tritempo, using wild-type (WT) and OST-resistant influenza strains. Cell-based assays in MDCKs were performed to confirm Tritempo`s antiviral activity and cytotoxicity. Multiple passages of the influenza virus in increasing concentrations of our compound, followed by the sequencing of NA gene and molecular docking, were used to identify our Tritempo's target. RESULTS AND DISCUSSION: Indeed, Tritempo inhibited the neuraminidase activity of WT and OSTresistant strains of influenza A and B, at the nanomolar range. Tritempo bound to WT and OST-resistant influenza NA isoforms at the sialic acid binding site with low free binding energies. Cell-free assays were confirmed using a prototypic influenza A infection assay in MDCK cells, in which we found an EC50 of 0.38 µM, along with very low cytotoxicity, CC50 > 2,000 µM. When we passaged the influenza A virus in the presence of Tritempo, a mutant virus with the G248P change in the NA was detected. This mutant was resistant to Tritempo but remained sensitive to OST, indicating no cross-resistance between the studied and reference drugs. CONCLUSION: Our results suggest that Tritempo's chemical structure is a promising one for the development of novel antivirals against influenza.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Piperidinas/farmacologia , Tiazóis/farmacologia , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
5.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842256

RESUMO

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 µM and 32.8 µM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 µM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.


Assuntos
Antivirais/farmacologia , Ácido Benzoico/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Ácido Benzoico/síntese química , Ácido Benzoico/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Replicação Viral/efeitos dos fármacos
6.
Biomed Khim ; 65(6): 520-525, 2019 Oct.
Artigo em Russo | MEDLINE | ID: mdl-31876523

RESUMO

The overall model for prediction of IC50 values for inhibitors of neuraminidase influenza virus A and B has been created. It combines data about IC50 values of complexes of 40 variants of neuraminidases of influenza A (7 serotypes) and B and three known inhibitors (oseltamivir, zanamivir, peramivir). The model also uses only data of enthalpy contributions to the potential energy of inhibitor/protein and substrate (MUNANA)/protein complexes. The calculation procedures are ported to use software with support of GPU accelerators, that significant decrease the computation time. The corresponding correlation coefficient (R²) for pIC50 prediction was within 0.45-0.58, the SEM values of around 0.7 (the range of used pIC50 data set is from 4.55 to 10.22).


Assuntos
Antivirais/química , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Ciclopentanos/química , Inibidores Enzimáticos/química , Guanidinas/química , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Oseltamivir/química , Zanamivir/química
7.
Res Vet Sci ; 127: 47-56, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31677416

RESUMO

Recent studies have questioned the effect of maternal derived antibodies (MDAs) to protect piglets against infection with influenza A virus (IAV). The lack of protection against IAV infections provided by MDAs has encouraged alternative vaccination strategies targeting young piglets in an attempt to stimulate an early antibody response. There is a lack of studies documenting the efficacy of piglet vaccination. In the present study, we monitored a group of vaccinated and non-vaccinated piglets in a Danish sow herd that initiated piglet vaccination with » dose of an inactivated swine influenza vaccine at the time of castration (day 3-4). A total of 160 piglets from 11 sows were included and either vaccinated with 0.5 mL inactivated swine influenza vaccine or sham-vaccinated. From week 0 until week 6, all included piglets were clinically examined and nasal swapped once per week and weighed at weeks 0, 3 and 6. Blood samples were collected from sows at week 0 and from piglets at week 3. Vaccination of piglets had limited effect on clinical signs, body weight, antibody development and viral shedding, within the first 6 weeks of life. At least 50% of all pigs of each treatment group tested positive for IAV at week 2, and very early onset of IAV shedding was observed. In total, 18 pigs were IAV positive in nasal swabs for more than one consecutive sampling time indicating prolonged shedding and 14 pigs were IAV positive with negative samplings in between indicating re-infection with the same IAV strain.


Assuntos
Vírus da Influenza A/efeitos dos fármacos , Vacinas contra Influenza/farmacologia , Infecções por Orthomyxoviridae/veterinária , Doenças dos Suínos/prevenção & controle , Vacinação/veterinária , Animais , Anticorpos Antivirais/sangue , Formação de Anticorpos , Dinamarca , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Suínos , Doenças dos Suínos/virologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/farmacologia , Eliminação de Partículas Virais
8.
J Biomed Sci ; 26(1): 84, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31640786

RESUMO

Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.


Assuntos
Antivirais/química , Desenvolvimento de Medicamentos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Desenho de Fármacos , Humanos
9.
Chem Biodivers ; 16(11): e1900315, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31532059

RESUMO

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


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , DNA/antagonistas & inibidores , Desenho de Fármacos , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Soroalbumina Bovina/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , DNA/química , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Hepacivirus/efeitos dos fármacos , Hidrazonas/síntese química , Hidrazonas/química , Vírus da Influenza A/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Soroalbumina Bovina/química
10.
Chin J Nat Med ; 17(9): 650-662, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31526500

RESUMO

Ge Gen Decoction (GGD), a Traditional Chinese Medicine prescription, is mainly used to treat infectious respiratory diseases and can relieve the symptoms of influenza A virus (IAV) infection. However, the underlying mechanism of GGD against IAV infection remains unclear. In this study, we found that GGD had moderate anti-IAV activity in vitro. GGD was more effective when given before the viral infection and targeted the viral attachment and replication stages rather than the internalization stage. In vivo, GGD treatment reduced thevirus titers of lung tissue significantly and improved the survival rate, lung index, and pulmonary histopathological changes in H1N1-infected mice. We observed the changes in several key immuno-related indexes in GGD administrated H1N1-infected mice with anti-IAV drug oseltamivir phosphate as the control. GGD treatment decreased the expression of TNF-α and improved Th1/Th2 immune balance to reduce the excessive immune response in H1N1-infected mice. Besides, the expression of the toll-like receptor 7 signaling pathway in H1N1-infected mice decreased after GGD treatment. Our results showed that GGD has anti-IAV activity and can modulate the immune system to relieve lung inflammation.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Animais , Antivirais/administração & dosagem , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Citocinas/metabolismo , Cães , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos ICR , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/administração & dosagem , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Equilíbrio Th1-Th2/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Ligação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
Biochimie ; 166: 203-213, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518617

RESUMO

Influenza A virus (IAV) is one of the most common infectious pathogen and associated with significant morbidity and mortality. Although processing the IAV hemagglutinin (HA) envelope glycoprotein precursor is a pre-requisite for viral membrane fusion activity, viral entry and transmission, HA-processing protease is not encoded in the IAV genome and thus the cellular trypsin-type serine HA-processing proteases determine viral infectious tropism and viral pathogenicity. The initial process of IAV infection of the airway is followed by marked upregulation of ectopic trypsin in various organs and endothelial cells through the induction of various proinflammatory cytokines, and this process has been termed the "influenza virus-cytokine-trypsin" cycle. In the advanced stage of IAV infection, the cytokine storm induces disorders of glucose and lipid metabolism and the "metabolic disorders-cytokine" cycle is then linked with the "influenza virus-cytokine-trypsin" cycle, to advance the pathogenic process into energy crisis and multiple organ failure. Application of protease inhibitors and treatment of metabolic disorders that break these cycles and their interconnection is therefore a promising therapeutic approach against influenza. This review discusses IAV pathogenicity on trypsin type serine HA-processing proteases, cytokines, metabolites and therapeutic options.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A , Influenza Humana , Serina Proteases/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Galinhas/virologia , Citocinas/metabolismo , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/patogenicidade , Influenza Aviária/tratamento farmacológico , Influenza Aviária/virologia , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Tripsina/metabolismo
12.
mSphere ; 4(5)2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533996

RESUMO

Both antiseptic hand rubbing (AHR) using ethanol-based disinfectants (EBDs) and antiseptic hand washing (AHW) are important means of infection control to prevent seasonal influenza A virus (IAV) outbreaks. However, previous reports suggest a reduced efficacy of ethanol disinfection against pathogens in mucus. We aimed to elucidate the situations and mechanisms underlying the reduced efficacy of EBDs against IAV in infectious mucus. We evaluated IAV inactivation and ethanol concentration change using IAV-infected patients' mucus (sputum). Additionally, AHR and AHW effectiveness against infectious mucus adhering to the hands and fingers was evaluated in 10 volunteers. Our clinical study showed that EBD effectiveness against IAV in mucus was extremely reduced compared to IAV in saline. IAV in mucus remained active despite 120 s of AHR; however, IAV in saline was completely inactivated within 30 s. Due to the low rate of diffusion/convection because of the physical properties of mucus as a hydrogel, the time required for the ethanol concentration to reach an IAV inactivation level and thus for EBDs to completely inactivate IAV was approximately eight times longer in mucus than in saline. On the other hand, AHR inactivated IAV in mucus within 30 s when the mucus dried completely because the hydrogel characteristics were lost. Additionally, AHW rapidly inactivated IAV. Until infectious mucus has completely dried, infectious IAV can remain on the hands and fingers, even after appropriate AHR using EBD, thereby increasing the risk of IAV transmission. We clarified the ineffectiveness of EBD use against IAV in infectious mucus.IMPORTANCE Antiseptic hand rubbing (AHR) and antiseptic hand washing (AHW) are important to prevent the spread of influenza A virus (IAV). This study elucidated the situations/mechanisms underlying the reduced efficacy of AHR against infectious mucus derived from IAV-infected individuals and indicated the weaknesses of the current hand hygiene regimens. Due to the low rate of diffusion/convection because of the physical properties of mucus as a hydrogel, the efficacy of AHR using ethanol-based disinfectant against mucus is greatly reduced until infectious mucus adhering to the hands/fingers has completely dried. If there is insufficient time before treating the next patient (i.e., if the infectious mucus is not completely dry), medical staff should be aware that effectiveness of AHR is reduced. Since AHW is effective against both dry and nondry infectious mucus, AHW should be adopted to compensate for these weaknesses of AHR.


Assuntos
Desinfetantes/farmacologia , Desinfecção das Mãos/normas , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/prevenção & controle , Muco/virologia , Etanol/farmacologia , Desinfecção das Mãos/métodos , Humanos , Controle de Infecções/métodos , Controle de Infecções/normas , Vírus da Influenza A/fisiologia , Influenza Humana/transmissão , Viabilidade Microbiana , Muco/efeitos dos fármacos , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/virologia
13.
Molecules ; 24(15)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382398

RESUMO

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.


Assuntos
Antivirais/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Penicillium/química , Antivirais/química , Produtos Biológicos/química , Linhagem Celular , HIV/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
14.
Eur J Med Chem ; 182: 111622, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425909

RESUMO

The development of entry inhibitors is an emerging approach to the inhibition of influenza virus. In our previous research, oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor. Herein, as a further study, we report the preparation of a series of OA-saccharide conjugates via the CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 11b, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC50 of 5.47 µM, and no obvious cytotoxic effect on MDCK cells was observed at 100 µM. Hemagglutination inhibition assay and docking experiment indicated that 11b might interfere with influenza virus infection by acting on HA protein. Broad-spectrum anti-influenza experiments showed 11b to be robustly potent against 5 different strains, including influenza A and B viruses, with IC50 values at the low-micromole level. Overall, this finding further extends the utility of OA-saccharide conjugates in anti-influenza virus drug design.


Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Vírus da Influenza A/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Oligossacarídeos/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Química Click , Cães , Relação Dose-Resposta a Droga , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Oligossacarídeos/síntese química , Oligossacarídeos/química , Relação Estrutura-Atividade
15.
Chem Pharm Bull (Tokyo) ; 67(11): 1201-1207, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31434835

RESUMO

Oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor in our earlier studies. In the present work, 20 compounds were prepared by structural modifications of OA, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in Madin-Darby canine kidney (MDCK) cells were evaluated. Based on the biological result, structure-activity relationship (SAR) was discussed. Compound 10 with six-carbon chain and a terminal hydroxyl group showed the strongest anti-influenza activity with an IC50 of 2.98 µM, which is an order of magnitude more potent than OA. Hemagglutination inhibition and Surface plasmon resonance (SPR) assay indicated that compound 10 might interfere with influenza invasion by interacting with HA protein.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Cães , Relação Dose-Resposta a Droga , Hemaglutininas/efeitos dos fármacos , Hemaglutininas/metabolismo , Vírus da Influenza A/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Estrutura Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
16.
Influenza Other Respir Viruses ; 13(5): 504-516, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31411006

RESUMO

BACKGROUND: Formulation of neuraminidase (NA) within influenza vaccines is gaining importance in light of recent human studies. The enzyme-linked lectin assay (ELLA) is considered a reliable assay to evaluate human anti-NA antibodies. OBJECTIVES: To overcome interference by hemagglutinin (HA)-specific antibodies and detect neuraminidase inhibitory (NI) antibodies only, two different sources of antigen have been studied in ELLA: reassortant viruses with a mismatched avian origin-HA or Triton X-100 (Tx)-treated wild-type viruses. Pseudotypes or pseudovirus (PV), characterized by a lentivirus core bearing human influenza NA and avian influenza HA, were investigated as an alternative source of antigen and compared to HA-mismatched and Tx-treated viruses, since represent a safer product to be handled. METHODS: Two independent panels of sera were analyzed by ELLA to evaluate the anti-NA response against N1 (A/California/07/2009 (H1N1pdm)) and N2 (A/Hong Kong/4801/2014 (H3N2)). The NA inhibition (NI) antibody titers measured as either the 50% end point or 50% inhibitory concentration (IC50 ) were compared for every source of antigen. RESULTS: The ELLA assay performed well with all three sources of antigen. NI titers measured using each antigen type correlated well when reported either as end point titers or as the IC50 . CONCLUSIONS: This study suggests that HA-mismatched whole virus, Triton-treated wild-type virus or PV can be used to measure NI antibody titers of human sera, but further comparability/validation assays should be performed to assess statistical differences. The data support the use of PV as an attractive alternative source of antigen and justify further investigation to improve stability of this antigen source.


Assuntos
Antígenos Virais/imunologia , Ensaios Enzimáticos/normas , Vírus da Influenza A/imunologia , Lectinas/química , Neuraminidase/imunologia , Octoxinol/farmacologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Aves/virologia , Ensaios Enzimáticos/métodos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A/efeitos dos fármacos , Vacinas contra Influenza/imunologia , Influenza Aviária/virologia , Influenza Humana/virologia , Lentivirus/genética , Lentivirus/imunologia , Neuraminidase/antagonistas & inibidores , Vírus Reordenados/genética , Vírus Reordenados/imunologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-31203585

RESUMO

As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a record total of 5866 human influenza positive samples during 2017. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties and were propagated in qualified cells and hens' eggs for use as potential seasonal influenza vaccine virus candidates. In 2017, influenza A(H3) viruses predominated over influenza A(H1)pdm09 and B viruses, accounting for a total of 54% of all viruses analysed. The majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2017. However, phylogenetic analysis indicated that the majority of circulating A(H3) viruses had undergone genetic drift relative to the WHO recommended vaccine strain for 2017. Of 3733 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, only two A(H1)pdm09 viruses and one A(H3) virus showed highly reduced inhibition by oseltamivir, while just one A(H1)pdm09 virus showed highly reduced inhibition by zanamivir.


Assuntos
Antígenos Virais/imunologia , Antivirais/farmacologia , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Animais , Austrália/epidemiologia , Galinhas , Cães , Farmacorresistência Viral , Ovos , Feminino , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/genética , Vírus da Influenza B/isolamento & purificação , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Células Madin Darby de Rim Canino , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Filogenia , Organização Mundial da Saúde , Zanamivir/farmacologia
18.
BMC Bioinformatics ; 20(1): 297, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159726

RESUMO

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


Assuntos
Antivirais/farmacologia , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Interações Hospedeiro-Patógeno , Mapas de Interação de Proteínas , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/metabolismo , RNA Interferente Pequeno/metabolismo , Reprodutibilidade dos Testes , Replicação Viral/efeitos dos fármacos
19.
Mol Pharmacol ; 96(2): 148-157, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175183

RESUMO

The Food and Drug Administration-approved influenza A antiviral amantadine inhibits the wild-type (WT) AM2 channel but not the S31N mutant predominantly found in circulating strains. In this study, serial viral passages were applied to select resistance against a newly developed isoxazole-conjugated adamantane inhibitor that targets the AM2 S31N channel. This led to the identification of the novel drug-resistant mutation L46P located outside the drug-binding site, which suggests an allosteric resistance mechanism. Intriguingly, when the L46P mutant was introduced to AM2 WT, the channel remained sensitive toward amantadine inhibition. To elucidate the molecular mechanism, molecular dynamics simulations and binding free energy molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed on WT and mutant channels. It was found that the L46P mutation caused a conformational change in the N terminus of transmembrane residues 22-31 that ultimately broadened the drug-binding site of AM2 S31N inhibitor 4, which spans residues 26-34, but not of AM2 WT inhibitor amantadine, which spans residues 31-34. The MM-GBSA calculations showed stronger binding stability for 4 in complex with AM2 S31N compared with 4 in complex with AM2 S31N/L46P, and equal binding free energies of amantadine in complex with AM2 WT and AM2 L46P. Overall, these results demonstrate a unique allosteric resistance mechanism toward AM2 S31N channel blockers, and the L46P mutant represents the first experimentally confirmed drug-resistant AM2 mutant that is located outside of the pore where drug binds. SIGNIFICANCE STATEMENT: AM2 S31N is a high-profile antiviral drug target, as more than 95% of currently circulating influenza A viruses carry this mutation. Understanding the mechanism of drug resistance is critical in designing the next generation of AM2 S31N channel blockers. Using a previously developed AM2 S31N channel blocker as a chemical probe, this study was the first to identify a novel resistant mutant, L46P. The L46P mutant is located outside of the drug-binding site. Molecular dynamics simulations showed that L46P causes a dilation of drug-binding site between residues 22 and 31, which affects the binding of AM2 S31N channel blockers, but not the AM2 WT inhibitor amantadine.


Assuntos
Amantadina/farmacologia , Antivirais/farmacologia , Vírus da Influenza A/metabolismo , Mutação , Proteínas da Matriz Viral/genética , Regulação Alostérica/efeitos dos fármacos , Motivos de Aminoácidos , Animais , Antivirais/química , Sítios de Ligação , Cães , Farmacorresistência Viral , Feminino , Humanos , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação Proteica , Inoculações Seriadas , Relação Estrutura-Atividade , Proteínas da Matriz Viral/química , Xenopus laevis
20.
PLoS One ; 14(5): e0217307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107922

RESUMO

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Replicação Viral/efeitos dos fármacos
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