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1.
Vet Ital ; 55(3): 195-201, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31599544

RESUMO

Each year millions of people are infected by influenza viruses, and this causes a substantial economic and health burden on our society. Influenza epidemics and pandemics are attributable to the ongoing evolution of influenza viruses through antigenic drift and shift, respectively. One of the reasons for the continuous circulation of influenza viruses in the human population is the incomplete protection conferred by currently available seasonal influenza vaccines against possible arising drifted or shifted influenza strains. Recently, tremendous efforts have been focused on the development of a more effective broadly reactive or universal influenza vaccine. The main objective of underdevelopment vaccines is to protect the human population not only from currently circulating virus strains but also from possible future variants without the need for their continuous update. Different approaches have been developed to reach this goal and elicit an effective and cross-protective immune response. Among these, consensus-based prophylactic approaches to effectively prevent influenza infections are the major focus of this review.


Assuntos
Hemaglutininas/uso terapêutico , Influenza Humana/prevenção & controle , Infecções por Orthomyxoviridae/veterinária , Orthomyxoviridae/efeitos dos fármacos , Animais , Humanos , Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/prevenção & controle
2.
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
3.
Eur J Med Chem ; 182: 111635, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493744

RESUMO

The discovery of novel potent neuraminidase (NA) inhibitors remains an attractive approach for treating infectious diseases caused by influenza. In this study, we describe the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NA. NA inhibitory studies showed that new derivatives demonstrated the inhibitory activity with IC50 values at nM level against NA of a clinical influenza virus strain. Moreover, the in silico ADME predictions showed that the selected compounds had comparable properties with oseltamivir carboxylate, which demonstrated the druggablity of these derivatives. Furthermore, molecular docking studies showed that the most potent compound 6f and 10i could adopt different modes of binding interaction with NA, which may provide novel solutions for treating oseltamivir-resistant influenza. Based on the research results, we consider that compounds 6f and 10i have the potential for further studies as novel antiviral agents.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Oseltamivir/farmacologia , Antivirais/síntese química , Antivirais/química , Simulação por Computador , Relação Dose-Resposta a Droga , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/enzimologia , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade
4.
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
5.
Drug Des Devel Ther ; 13: 1059-1068, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040643

RESUMO

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


Assuntos
Peptídeos Penetradores de Células/farmacologia , Galanina/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/crescimento & desenvolvimento , RNA Interferente Pequeno/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Replicação Viral/efeitos dos fármacos , Venenos de Vespas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Galanina/química , Células Madin Darby de Rim Canino , RNA Interferente Pequeno/química , Proteínas Recombinantes de Fusão/química , Venenos de Vespas/química
7.
Carbohydr Res ; 477: 32-38, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30954773

RESUMO

A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 Šcan crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.


Assuntos
Antivirais/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Oseltamivir/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/enzimologia , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade
8.
Expert Opin Investig Drugs ; 28(5): 481-488, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31018720

RESUMO

INTRODUCTION: Influenza viral ribonucleoprotein complexes (vRNPs) play a key role in viral transcription and replication; hence, the recent development of novel anti-influenza drugs targeting vRNPs has garnered widespread interest. AREAS COVERED: We discuss the function of the constituents of vRNPs and summarize those vRNPs-targeted synthetic drugs that are in preclinical and early clinical development. EXPERT OPINION: vRNPs contain high-value drug targets; such targets include the subunits PA, PB1, PB2, and NP. Developing a new generation of antiviral therapies with strategies that utilize existing drugs, natural compounds originated from new resources and novel drug combinations may open up new therapeutic approaches to influenza.


Assuntos
Antivirais/farmacologia , Desenvolvimento de Medicamentos , Influenza Humana/tratamento farmacológico , Animais , Antivirais/administração & dosagem , Quimioterapia Combinada , Drogas em Investigação/farmacologia , Humanos , Influenza Humana/virologia , Terapia de Alvo Molecular , Orthomyxoviridae/efeitos dos fármacos , Ribonucleoproteínas/isolamento & purificação
9.
Eur J Med Chem ; 173: 305-313, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022584

RESUMO

Neuraminidase (NA) plays a crucial role in the replication and transmission of influenza virus. NA inhibitors have been developed as effective treatments for influenza A and B infections. In this paper, a new lead neuraminidase inhibitor 6a (IC50 = 7.10 ±â€¯0.2 µM) was discovered by ligand-based virtual screening, receptor-based virtual screening, molecular dynamics simulation (MD), and bioassay validation. MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA. To exploit the 430-loop in the active site, a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a. Compound 6e exerts the most potency, with IC50 value of 2.37 ±â€¯0.5 µM against NA, which is lower than that of oseltamivir carboxylate (OC) (IC50 = 3.84 µM). Overall, this work provided unique insights in the discovery of potent inhibitors against NA.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/enzimologia , Relação Estrutura-Atividade
10.
Emerg Microbes Infect ; 8(1): 339-352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866787

RESUMO

Acute undifferentiated fever (AUF) is frequently observed in tropical settings, but diagnosing the cause of AUF is often a challenge for local physicians and the physicians treating returning travellers. We conducted a case-control study in central Vietnam in 2016. A total of 378 febrile adult patients (AUFs) with a fever for ≤21 days, no evidence of localized infection and negative screening tests for dengue and malaria, and 384 afebrile adult patients (Controls) were prospectively enrolled. Whole blood, plasma, eschar swab, throat swab and urine specimens were collected and analysed. Quantitative PCR and RT-PCR were used to test for 55 bacteria, viruses and their subtypes. Serological tests were also used to test for rickettsial agents. The most common aetiology was influenza virus (20.9% in AUFs vs. 0% in Controls), followed by rickettsial agents (mainly Orientia tsutsugamushi and Rickettsia typhi) (10.8% vs. 0.3%), dengue virus (7.7% vs. 0.5%), Leptospira (4.8% vs. 0.8%), adenovirus (4.8% vs. 1.0%), and enterovirus (2.1% vs. 0%) (p < .05). The real proportion of dengue in AUF cases was underestimated because patients with dengue-positive rapid diagnosis tests were excluded from the study. The emerging agent Rickettsia felis, which had not been previously observed in Vietnam, was detected in this study. In total, 216 patients (57.1%) were given causative diagnoses, comprising 143 (66.2%) monoinfections and 73 (33.8%) coinfections. The infections caused by these agents should be considered in clinical practice and further studies. Additionally, agents susceptible to doxycycline were detected in 15.6% of AUFs; thus, this drug should be included in the panel used to treat AUF patients.


Assuntos
Bactérias/classificação , Coinfecção/epidemiologia , Febre/etiologia , Vírus/classificação , Adulto , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Casos e Controles , Coinfecção/microbiologia , Doxiciclina/farmacologia , Feminino , Febre/sangue , Febre/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/isolamento & purificação , Estudos Prospectivos , Rickettsia/efeitos dos fármacos , Rickettsia/isolamento & purificação , Vietnã/epidemiologia , Vírus/efeitos dos fármacos , Vírus/genética , Vírus/isolamento & purificação
11.
Cell Struct Funct ; 44(1): 61-74, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30905923

RESUMO

Endocytosis mediates the internalization and ingestion of a variety of endogenous or exogenous substances, including virus particles, under the control of intracellular signaling pathways. We have previously reported that the complex formed between the small GTPase Ras and phosphoinositide 3-kinase (PI3K) translocates from the plasma membrane to endosomes, signaling from which thereby regulates clathrin-independent endocytosis, endosome maturation, influenza virus internalization, and infection. However, the molecular mechanism by which the Ras-PI3K complex is recruited to endosomes remains unclear. Here, we have identified the amino acid sequence responsible for endosomal localization of the Ras-PI3K complex. PI3K lacking this sequence failed to translocate to endosomes, and expression of the peptide comprising this PI3K-derived sequence inhibited clathrin-independent endocytosis, influenza virus internalization, and infection. Moreover, treatment of cells with this peptide in an arginine-rich, cell-penetrating form successfully suppressed influenza virus infection in vitro and ex vivo, making this peptide a potential therapeutic agent against influenza virus infection.Key words: signal transduction, endocytosis, endosome, imaging, influenza virus.


Assuntos
Endocitose/efeitos dos fármacos , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/fisiologia , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinase/química , Sequência de Aminoácidos , Animais , Linhagem Celular , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Humanos , Fragmentos de Peptídeos/química , Transporte Proteico/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Proteínas ras/metabolismo
12.
Bioconjug Chem ; 30(3): 931-943, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30721034

RESUMO

RNAs play critical roles in diverse catalytic and regulatory biological processes and are emerging as important disease biomarkers and therapeutic targets. Thus, developing chemical compounds for targeting any desired RNA structures has great potential in biomedical applications. The viral and cellular RNA sequence and structure databases lay the groundwork for developing RNA-binding chemical ligands through the recognition of both RNA sequence and RNA structure. Influenza A virion consists of eight segments of negative-strand viral RNA (vRNA), all of which contain a highly conserved panhandle duplex structure formed between the first 13 nucleotides at the 5' end and the last 12 nucleotides at the 3' end. Here, we report our binding and cell culture anti-influenza assays of a short 10-mer chemically modified double-stranded RNA (dsRNA)-binding peptide nucleic acid (PNA) designed to bind to the panhandle duplex structure through novel major-groove PNA·RNA2 triplex formation. We demonstrated that incorporation of chemically modified PNA residues thio-pseudoisocytosine (L) and guanidine-modified 5-methyl cytosine (Q) previously developed by us facilitates the sequence-specific recognition of Watson-Crick G-C and C-G pairs, respectively, at physiologically relevant conditions. Significantly, the chemically modified dsRNA-binding PNA (dbPNA) shows selective binding to the dsRNA region in panhandle structure over a single-stranded RNA (ssRNA) and a dsDNA containing the same sequence. The panhandle structure is not accessible to traditional antisense DNA or RNA with a similar length. Conjugation of the dbPNA with an aminosugar neamine enhances the cellular uptake. We observed that 2-5 µM dbPNA-neamine conjugate results in a significant reduction of viral replication. In addition, the 10-mer dbPNA inhibits innate immune receptor RIG-I binding to panhandle structure and thus RIG-I ATPase activity. These findings would provide the foundation for developing novel dbPNAs for the detection of influenza viral RNAs and therapeutics with optimal antiviral and immunomodulatory activities.


Assuntos
Orthomyxoviridae/efeitos dos fármacos , Ácidos Nucleicos Peptídicos/química , Ácidos Nucleicos Peptídicos/farmacologia , RNA de Cadeia Dupla/metabolismo , RNA Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Dicroísmo Circular , Cães , Células Madin Darby de Rim Canino , Eletroforese em Gel de Poliacrilamida Nativa , Conformação de Ácido Nucleico , Orthomyxoviridae/genética , Orthomyxoviridae/fisiologia , RNA de Cadeia Dupla/química
13.
J Gen Virol ; 100(4): 583-601, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30762518

RESUMO

The possible resistance of influenza virus against existing antiviral drugs calls for new therapeutic concepts. One appealing strategy is to inhibit virus entry, in particular at the stage of internalization. This requires a better understanding of virus-host interactions during the entry process, including the role of receptor tyrosine kinases (RTKs). To search for cellular targets, we evaluated a panel of 276 protein kinase inhibitors in a multicycle antiviral assay in Madin-Darby canine kidney cells. The RTK inhibitor Ki8751 displayed robust anti-influenza A and B virus activity and was selected for mechanistic investigations. Ki8751 efficiently disrupted the endocytic process of influenza virus in different cell lines carrying platelet-derived growth factor receptor ß (PDGFRß), an RTK that is known to act at GM3 ganglioside-positive lipid rafts. The more efficient virus entry in CHO-K1 cells compared to the wild-type ancestor (CHO-wt) cells indicated a positive effect of GM3, which is abundant in CHO-K1 but not in CHO-wt cells. Entering virus localized to GM3-positive lipid rafts and the PDGFRß-containing endosomal compartment. PDGFRß/GM3-dependent virus internalization involved PDGFRß phosphorylation, which was potently inhibited by Ki8751, and desialylation of activated PDGFRß by the viral neuraminidase. Virus uptake coincided with strong activation of the Raf/MEK/Erk cascade, but not of PI3K/Akt or phospholipase C-γ. We conclude that influenza virus efficiently hijacks the GM3-enhanced PDGFRß signalling pathway for cell penetration, providing an opportunity for host cell-targeting antiviral intervention.


Assuntos
Gangliosídeo G(M3)/metabolismo , Influenza Humana/metabolismo , Influenza Humana/virologia , Infecções por Orthomyxoviridae/metabolismo , Orthomyxoviridae/patogenicidade , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Animais , Células CHO , Linhagem Celular , Cricetulus , Cães , Células HEK293 , Humanos , Influenza Humana/tratamento farmacológico , Células Madin Darby de Rim Canino , Orthomyxoviridae/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
14.
Rev. esp. quimioter ; 32(1): 1-5, feb. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-182741

RESUMO

Baloxavir marboxil (ácido 5-hidroxi-4-piridona-3-carboxilo) es un nuevo fármaco antiviral con especial eficacia sobre los virus gripales que actúa inhibiendo la endonuclease cap-dependiente que precisan para su replicación. Es el primer representante de los denominados inhibidores de la proteína básica 2 (PB2) gripal. Ha mostrado eficacia frente a los virus gripales A y B y la mayoría de cepas de origen animal (gripe aviar). Los ensayos clínicos realizados en pacientes sanos de entre 12 y 64 años sin patologías y no hospitalizados (gripe leve) han mostrado una reducción de la duración de la sintomatología parecida a la obtenida por oseltamivir. Sin embargo baloxavir es un inhibidor de la replicación viral mucho más potente que este fármaco. Se ha mostrado como un fármaco seguro y bien tolerado. Se administra una sola dosis de 40-80 mg las primeras 48 horas del inicio de los síntomas. En estos ensayos se han detectado cepas con sensibilidad moderada (mutantes PA/I38T) en el 2,2% de la gripe A (H1N1)pdm09 y en el 9,7% de la gripe A (H3N2). A pesar de estos datos podría ser un buen fármaco para tratar la gripe leve o moderada, precisando de ensayos en gripe grave y pacientes con patologías crónicas para establecer su verdadera utilidad clínica


Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility


Assuntos
Humanos , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Antivirais/farmacocinética , Orthomyxoviridae/efeitos dos fármacos , Inibidores Enzimáticos/farmacocinética , Medicamentos Compostos contra Resfriado, Influenza e Alergia/farmacocinética , Resultado do Tratamento
18.
Rev Esp Quimioter ; 32(1): 1-5, 2019 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-30676002

RESUMO

Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility.


Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/enzimologia , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Antivirais/farmacologia , Criança , Feminino , Humanos , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Adulto Jovem
19.
Eur J Med Chem ; 161: 526-532, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30390440

RESUMO

A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series.


Assuntos
Antivirais/farmacologia , Derivados de Benzeno/farmacologia , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Imidazolinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Derivados de Benzeno/química , Cães , Relação Dose-Resposta a Droga , Endonucleases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Imidazolinas/síntese química , Imidazolinas/química , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/microbiologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Orthomyxoviridae/enzimologia , Relação Estrutura-Atividade
20.
Int J Nanomedicine ; 13: 8579-8593, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30587980

RESUMO

Background: Influenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application. Methods: In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs' anti-influenza applicability. Results: Using PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater in vitro antiviral activity, improving the therapeutic index of diphyllin and bafilomycin by approximately 3 and 5-fold, respectively. In a mouse model of sublethal influenza challenge, treatment with diphyllin nanoparticles resulted in reduced body weight loss and viral titer in the lungs. In addition, following a lethal influenza viral challenge, diphyllin nanoparticle treatment conferred a survival advantage of 33%. Conclusions: These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Nanopartículas/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacologia , Benzodioxóis/química , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Linhagem Celular , Cães , Liberação Controlada de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/virologia , Concentração Inibidora 50 , Cinética , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Macrolídeos/química , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Camundongos , Nanopartículas/ultraestrutura , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
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