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1.
Acta Virol ; 63(3): 309-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507197

RESUMO

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia. Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.


Assuntos
Amidas , Antivirais , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Pirazinas , Tripsina , Amidas/farmacologia , Antivirais/farmacologia , Linhagem Celular , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Oseltamivir/farmacologia , Pirazinas/farmacologia , RNA Viral/biossíntese , Tripsina/farmacologia
2.
Virol J ; 16(1): 87, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266524

RESUMO

BACKGROUND: Human infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied. METHODS: Thirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells. RESULTS: Four potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P<0.05). Rg006-NA119V, rg006-NA246T or rg006-NA274Y showed comparable replication capacity to wild-type virus (except for rg006-NA274Y at 96 h, P<0.05). CONCLUSIONS: All 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of HPAI H7N9 to NAIs. The NAI-resistant mutations in HPAI H7N9, in most cases, did not reduce the replication ability of the virus in mammalian cells. Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/virologia , Replicação Viral/efeitos dos fármacos , Substituição de Aminoácidos , Animais , Galinhas , Cães , Farmacorresistência Viral/genética , Humanos , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Aviária , Células Madin Darby de Rim Canino , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Zanamivir/farmacologia
3.
Vet Microbiol ; 235: 21-24, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282375

RESUMO

Occurrence of avian influenza (AI) with Neuraminidase (NA) mutations which confer reduced neuraminidase inhibitor (NAI) susceptibility has remained a cause of concern. The susceptibility to NAIs of 67 highly pathogenic avian influenza H5N1 viruses isolated during 2006-2012 in India was tested in phenotypic fluorescence-based NA inhibition assay, sequence analysis and in ovo. One isolate showed a novel NA I117T amino acid substitution (N2 numbering) and eight isolates showed previously known NAI-resistance marker mutations (I117V, E119D, N294S, total 9/67). The overall incidence of resistant variants was 13.4%. The novel I117T substitution reduced oseltamivir susceptibility by 18.6-fold and zanamivir susceptibility by 11.8-fold, compared to the wild type AI H5N1virus, thus showed cross-resistance to both oseltamivir and zanamivir in NA inhibition assays. However, the other two isolates with I117V substitution were sensitive to both the NAIs. In addition, the comparison of growth of the I117T and I117V variants in presence of NAI's in the in ovo assays exhibited difference in growth levels. The present study reports the natural occurrence of a novel I117T mutation in AI H5N1 virus conferring cross-resistance to oseltamivir and zanamivir highlighting the urgent need of antiviral surveillance of AI viruses.


Assuntos
Antivirais/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/genética , Oseltamivir/farmacologia , Proteínas Virais/genética , Zanamivir/farmacologia , Substituição de Aminoácidos , Animais , Galinhas , Farmacorresistência Viral , Índia , Virus da Influenza A Subtipo H5N1/genética , Concentração Inibidora 50 , Mutação de Sentido Incorreto , Zigoto
4.
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
5.
Eur J Med Chem ; 178: 64-80, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176096

RESUMO

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 µM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Domínio Catalítico , Linhagem Celular , Galinhas , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Feminino , Influenzavirus A/enzimologia , Influenzavirus B/enzimologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Neuraminidase/química , Oseltamivir/síntese química , Oseltamivir/toxicidade , Proteínas Virais/química
6.
Yakugaku Zasshi ; 139(5): 767-781, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31061347

RESUMO

Although the anti-influenza virus drug oseltamivir ameliorates the fever of influenza, adverse events related to its hypothermic effect have been reported. We found that oseltamivir causes dose-dependent hypothermia in normal mice, and have been studying the pharmacological mechanisms responsible for 12 years. Oseltamivir blocks nicotinic cholinergic transmission at sympathetic ganglia and reduces sympathetic modulation of brown adipose tissue (BAT), a heat generator. Oseltamivir was found to target the ion channels of nicotinic acetylcholine receptors, as demonstrated by patch clamp experiments with cells expressing the human α3ß4 nicotinic receptor. Metabolized oseltamivir carboxylate, which inhibits the influenza virus neuraminidase, did not elicit hypothermia and ion channel suppression. Body temperature was decreased by intracerebroventricular administration of oseltamivir. Because this hypothermic effect was inhibited by dopamine D2 receptor blockade, it was suggested that oseltamivir centrally stimulates the D2 receptor. In Japan, the package inserts for oseltamivir and amantadine indicate very similar adverse neuropsychiatric reactions for the two drugs (abnormal behavior, consciousness disturbance, convulsion, delirium, delusion, hallucination). A literature search revealed that in some previous studies, oseltamivir and amantadine were shown to block the ion channel systems and activate the dopaminergic nervous system via several mechanisms. Therefore the similarity of the adverse reactions elicited by oseltamivir and amantadine was considered attributable to their similar pharmacological effects.


Assuntos
Antipiréticos , Hipotermia/induzido quimicamente , Oseltamivir/efeitos adversos , Oseltamivir/farmacologia , Tecido Adiposo Marrom/metabolismo , Amantadina , Animais , Antivirais , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Oseltamivir/metabolismo , Ratos , Receptores de Dopamina D2/metabolismo , Receptores Nicotínicos/metabolismo
8.
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
9.
Virus Res ; 265: 122-126, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30910698

RESUMO

Identification of amino-acid substitutions in the neuraminidase (NA) of low-pathogenic avian influenza (AI) H9N2 viruses is important to study the susceptibility to NA inhibitors (NAI). To identify mutations under NAI selective pressure, the virus was serially passaged with increasing levels of either oseltamivir or zanamivir in ovo, and the growth of the viruses in the presence and absence of NAI's compared. Mutations R292 K in the presence of oseltamivir and E119D in presence of zanamivir were observed within passage one and two respectively. The R292 K mutation reduced oseltamivir susceptibility significantly (2,523-fold) and moderately reduced susceptibility to zanamivir. The E119D mutation significantly reduced susceptibility to zanamivir (415-fold) and remained susceptible to oseltamivir. Genetic stability of the mutations assessed by serial passages of the mutant viruses in eggs without drug pressure resulted in the loss of these mutations, making the virus susceptible to both the drugs. Molecular modeling and dynamics simulations revealed that the R292 K mutation disrupted oseltamivir binding similar to other group 2 NAs, while a different mechanism was noted for zanamivir binding for both R292 K and E119D mutations. The study highlights the need for regular susceptibility screening of circulating AI viruses.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H9N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H9N2/genética , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Zanamivir/farmacologia , Substituição de Aminoácidos , Animais , Embrião de Galinha , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Dinâmica Molecular , Mutação
10.
Emerg Med J ; 36(1): 55-56, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30635346

RESUMO

A short cut review was carried out to establish whether Oseltamivir leads to faster alleviation of symptoms, fewer hospital admissions and lower mortality in adult patients with confirmed influenza B presenting to the Emergency Department. Two studies were directly relevant to the question using the described search methodology on Ovid Medline and Embase. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line: there is no good evidence that oseltamivir results in quicker alleviation of symptoms, fewer hospital admissions or lower mortality in adult patients with influenza B.


Assuntos
Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Oseltamivir/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Tosse/etiologia , Serviço Hospitalar de Emergência/organização & administração , Medicina de Emergência Baseada em Evidências/métodos , Fadiga/etiologia , Humanos , Vírus da Influenza B/patogenicidade , Masculino , Pessoa de Meia-Idade , Oseltamivir/uso terapêutico
11.
Int J Biol Macromol ; 125: 931-940, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30572041

RESUMO

Albumin immobilized nanoparticles are known to be biodegradable, easy to prepare and reproducible for drug delivery systems. In summary, we have synthesized a new drug carrier using modified iron oxide nanoparticles. The synthesized drug carrier was characterized by X-ray powder diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), Fourier transform infrared (FT-IR), vibrating sample magnetometry (VSM) and energy-dispersive X-ray spectroscopy (EDX). Three different drugs were loaded on the modified iron oxide nanoparticles and then human serum albumin (HSA) immobilized on the iron oxide nanoparticles. In addition, the in-vitro antiproliferative activity of Fe3O4@SiO2@Nev@HSA nanoparticles against Hela cancer cell line using MTT colourimetric assay was compared with nevirapine. The results show that Fe3O4@SiO2@Nev@HSA nanoparticles in comparison to nevirapine itself have more effective antiproliferative activity on Hela cancer cell lines. The IC50 value for Fe3O4@SiO2@Nev@HSA nanoparticles was 59.20 µg/ml, which is close to the antiproliferative activity of anti-cancer gefitinib with IC50 value of 76.24 µg/ml. Moreover, in vitro calf thymus DNA (ct-DNA) binding studies were investigated by various spectroscopy techniques.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos , Composição de Medicamentos/métodos , Óxido Ferroso-Férrico/química , Gefitinibe/farmacologia , Nanopartículas de Magnetita/química , Albumina Sérica Humana/química , Animais , Antineoplásicos/química , Antivirais/química , Antivirais/farmacologia , Proliferação de Células/efeitos dos fármacos , Cercopithecus aethiops , DNA/química , Estabilidade de Medicamentos , Gefitinibe/química , Células HeLa , Humanos , Proteínas Imobilizadas/química , Concentração Inibidora 50 , Nanopartículas de Magnetita/ultraestrutura , Nevirapina/química , Nevirapina/farmacologia , Especificidade de Órgãos , Oseltamivir/química , Oseltamivir/farmacologia , Dióxido de Silício/química , Tenofovir/química , Tenofovir/farmacologia , Células Vero
12.
Int J Clin Pharmacol Ther ; 57(3): 152-159, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30526812

RESUMO

OBJECTIVE: Neuraminidase (sialidase) inhibitors are considered to delay platelet clearance through the inhibition of platelet desialylation. A novel neuraminidase inhibitor, peramivir, was recently approved for intravenous administration by the US FDA. We aimed to compare the effects of peramivir and oseltamivir on patient platelet count. MATERIALS AND METHODS: Consecutive patients who were treated with peramivir or tested positive for influenza between January 2015 and December 2017 were analyzed. The analysis included 461 patients with platelet counts available; the patients were divided into three groups: patients with proven influenza treated with peramivir (n = 305); those treated with peramivir without proven influenza (n = 83), and those with proven influenza treated with oseltamivir (n = 73). RESULTS: Patients treated with peramivir did not show an increase in platelet count from the baseline count, regardless of proven influenza (from 263.4 × 109/L to 267.4 × 109/L; 9 = 0.410) or not (from 257.1 × 109/L to 255.4 × 109/L; p = 0.873); wheeras for patients treated with oseltamivir, a significant increase above the baseline was found (from 223.3 × 109/L to 249.9 × 109/L; p = 0.016), although it was transient. CONCLUSION: Peramivir and oseltamivir appear to have different effects on patient platelet count when administered at the recommended doses.
.


Assuntos
Antivirais/farmacologia , Ciclopentanos/farmacologia , Guanidinas/farmacologia , Influenza Humana/tratamento farmacológico , Oseltamivir/farmacologia , Contagem de Plaquetas , Humanos
13.
Chem Commun (Camb) ; 54(76): 10691-10694, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30187046
14.
Yakugaku Zasshi ; 138(9): 1201-1215, 2018 Sep 01.
Artigo em Japonês | MEDLINE | ID: mdl-29925727

RESUMO

 The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as "clinically significant adverse reactions", and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.


Assuntos
Amantadina/efeitos adversos , Antivirais/efeitos adversos , Rotulagem de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Transtornos Mentais/induzido quimicamente , Doenças do Sistema Nervoso/induzido quimicamente , Oseltamivir/efeitos adversos , Amantadina/química , Amantadina/farmacologia , Antivirais/química , Antivirais/farmacologia , Agonistas de Dopamina , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/tratamento farmacológico , Conformação Molecular , Neuraminidase/antagonistas & inibidores , Antagonistas Nicotínicos , Oseltamivir/química , Oseltamivir/farmacologia
15.
Chem Commun (Camb) ; 54(54): 7467-7470, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29915822

RESUMO

Among a series of chemically synthesized fucoidan derivatives (1-9), 5 was found for the first time to bind to influenza virus hemagglutinins (HAs) and inhibit hemagglutination activity. In addition, a designed C3-symmetric tripodal ligand 10, synthesized with three sulfated oligofucoside moieties of 5, exhibited much greater hemagglutination inhibition activity than 5. A plaque assay using MDCK cells demonstrated that 10 effectively inhibited influenza virus infection.


Assuntos
Antivirais/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacologia , Animais , Galinhas , Cães , Fucus , Hemaglutinação por Vírus/efeitos dos fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Vírus da Influenza A Subtipo H1N1/metabolismo , Vírus da Influenza A Subtipo H3N2/metabolismo , Ligantes , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Oligossacarídeos/síntese química , Oligossacarídeos/química , Oseltamivir/farmacologia , Ligação Proteica
16.
Eur J Med Chem ; 154: 314-323, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29843102

RESUMO

Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.


Assuntos
Antivirais/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oseltamivir/farmacologia , Pró-Fármacos/farmacologia , Zanamivir/farmacologia , Administração Oral , Antivirais/administração & dosagem , Antivirais/química , Relação Dose-Resposta a Droga , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Oseltamivir/administração & dosagem , Oseltamivir/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Relação Estrutura-Atividade , Zanamivir/administração & dosagem , Zanamivir/química
17.
Arch Pharm Res ; 41(6): 664-676, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29572682

RESUMO

Baicalin was identified as a neuraminidase (NA) inhibitor displaying anti-influenza A virus (IAV) activity. However, its poor solubility in saline has limited its use in the clinic. We generated sodium baicalin and showed that it exhibited greatly increased solubility in saline. Its efficacy against oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) was evaluated in vitro and in vivo. Results showed that 10 µM of sodium baicalin inhibited A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and H1N1-H275Y in MDCK cells in a dose-dependent manner, with inhibitory rates of 83.9, 75.9 and 47.7%, respectively. Intravenous administration of sodium baicalin at 100 mg/kg/d enabled the survival of 20% of H1N1-H275Y-infected mice. The treatment alleviated body weight loss and lung injury. Moreover, sodium baicalin exerted a clear inhibitory effect on NAs. The IC50 values of sodium baicalin against H1N1-H275Y and cells-expressing A/Anhui/1/2013-R294K (H7N9-R294K) NA protein (N9-R294K) were 214.4 µM and 216.3 µM. Direct interactions between sodium baicalin and NA were observed, and we simulated the interactions of sodium baicalin with N9-R294K and N9 near the active sites of OC-N9-R294K and OC-N9. The residues responsible for the sodium baicalin-N9-R294K and sodium baicalin-N9 interactions were the same, confirming that sodium baicalin exerts effects on wild-type and oseltamivir-resistant viral strains.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Administração Intravenosa , Animais , Antivirais/uso terapêutico , Células CHO , Cricetulus , Modelos Animais de Doenças , Cães , Farmacorresistência Viral , Inibidores Enzimáticos/uso terapêutico , Flavonoides/uso terapêutico , Humanos , Vírus da Influenza A/genética , Influenza Humana/mortalidade , Influenza Humana/virologia , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Scutellaria/química , Replicação Viral/efeitos dos fármacos
18.
Eur J Med Chem ; 146: 220-231, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407952

RESUMO

Inspired by our initial discovery about a series of neuraminidase (NA) inhibitors targeting the 150-cavity, in present study, we designed, synthesized, and biologically tested a panel of novel oseltamivir derivatives with C-1 modification, targeting the 430-cavity, an additional binding site which widely and stably existed in both group-1 and group-2 NAs. Some of the synthesized compounds displayed robust anti-influenza potencies against H5N1 and H5N6 viruses. Among them, compound 8b exerted the greatest inhibition, with IC50 values of 0.088 and 0.097 µM and EC50 values of 4.26 and 1.31 µM against H5N1 and H5N6 strains, respectively, which are similar to those of oseltamivir carboxylate (OSC). And its potency against mutant H5N1-H274Y NA was just 7-fold weaker than OSC. Molecular modeling revealed the elongated group at C-1 position being projected toward the 430-cavity. Notably, although compound 8b was not sensitive toward H5N1 strain relative to OSC in the embryonated egg model, it displayed greater anti-influenza virus effect against H5N6 strain than OSC at the concentration of 10 mmol/L. Overall, this work provided unique insights in the discovery of potent inhibitors against both group-1 and group-2 NAs.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha/efeitos dos fármacos , Embrião de Galinha/virologia , Galinhas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Neuraminidase/metabolismo , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade
19.
Biotechnol Lett ; 40(5): 755-763, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29464570

RESUMO

OBJECTIVES: The aim of the study is to generate a spherical three-dimensional (3D) aggregate of hepatocyte-like cells (HLCs) differentiated from human embryonic stem cells and to investigate the effect of the 3D environment on hepatic maturation and drug metabolism. RESULTS: Quantitative real-time PCR analysis indicated that gene expression of mature hepatocyte markers, drug-metabolizing enzymes, and hepatic transporters was significantly higher in HLCs cultured in the 3D system than in those cultured in a two-dimensional system (p < 0.001). Moreover, hepatocyte-specific functions, including albumin secretion and bile canaliculi formation, were increased in HLCs cultured in the 3D system. In particular, 3D spheroidal culture increased expression of CES1 and BCHE, which encode hepatic esterases (p < 0.001). The enhanced activities of these hepatic esterases were confirmed by the cholinesterase activity assay and the increased susceptibility of HLCs to oseltamivir, which is metabolized by CES1. CONCLUSIONS: 3D spheroidal culture enhances the maturation and drug metabolism of stem cell-derived HLCs, and this may help to optimize hepatic differentiation protocols for hepatotoxicity testing.


Assuntos
Butirilcolinesterase/genética , Hidrolases de Éster Carboxílico/genética , Técnicas de Cultura de Células/métodos , Hepatócitos/citologia , Células-Tronco Embrionárias Humanas/citologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Oseltamivir/farmacologia , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
J Pharmacol Sci ; 136(1): 39-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29292053

RESUMO

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D2-selective antagonist L-741,626, but not by D1/D5-selective and D3-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D2 receptors.


Assuntos
Antivirais/farmacologia , Hipotermia/induzido quimicamente , Oseltamivir/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Antivirais/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Camundongos Endogâmicos , Oseltamivir/administração & dosagem , Oseltamivir/antagonistas & inibidores
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