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1.
J Hepatol ; 49(6): 908-15, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18845353

RESUMO

BACKGROUND/AIMS: The development of new therapies for hepatitis C virus (HCV) infection has been hampered by the lack of a small animal model. GB virus B (GBV-B), which infects new world monkeys, has been proposed as a surrogate system for HCV replication. Despite their short genetic distance, however, difficulties exist when extrapolating results from GBV-B to the HCV system. One way of addressing this is the creation of chimeric GBV-B containing HCV elements. METHODS: Construction and analysis of GBV-B chimeras in which the p13 ion channel was replaced by its HCV counterpart, p7. RESULTS: Replacing all, or part of, the GBV-B p13 protein with HCV p7 resulted in viable chimeras which replicated at wild-type levels in marmosets following intra-hepatic RNA injection. Serum from one animal injected with chimeric RNA was infectious in three naïve recipients, indicating that chimeras formed fully infectious virions. Amantadine, which blocks the ion channel activity of both HCV and GBV-B proteins in vitro, also inhibited GBV-B replication in primary hepatocytes. CONCLUSIONS: These viruses highlight the potential for chimeric GBV-B in the development of HCV-specific therapies and will provide a means of developing HCV p7 as a therapeutic target.


Assuntos
Vírus GB B/genética , Hepacivirus/genética , Hepatite C Crônica/virologia , Proteínas Recombinantes de Fusão/genética , Proteínas Virais/genética , Amantadina/farmacologia , Animais , Antivirais/farmacologia , Callithrix , Linhagem Celular , Modelos Animais de Doenças , Desenho de Fármacos , Genoma Viral , Hepatite C Crônica/tratamento farmacológico , Hepatócitos/citologia , Hepatócitos/virologia , Humanos , Rim/citologia , RNA Viral/sangue , RNA Viral/genética , Transfecção
4.
J Med Chem ; 48(8): 2964-71, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828835

RESUMO

The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.


Assuntos
Antivirais/síntese química , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/prevenção & controle , Ácidos Siálicos/química , Ácidos Siálicos/síntese química , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Linhagem Celular , Cristalização , Dimerização , Guanidinas , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/virologia , Masculino , Membranas Artificiais , Camundongos , Modelos Moleculares , Peso Molecular , Infecções por Orthomyxoviridae/virologia , Piranos , Ratos , Ratos Sprague-Dawley , Ácidos Siálicos/farmacocinética , Ácidos Siálicos/farmacologia , Estereoisomerismo , Ensaio de Placa Viral , Zanamivir
5.
Antimicrob Agents Chemother ; 49(4): 1381-90, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15793116

RESUMO

A recombinant vaccinia virus, expressing the NS3-to-NS5 region of the N clone of hepatitis C virus (HCV), was generated and utilized both in a gel-based assay and in an enzyme-linked immunosorbent assay (ELISA) to evaluate the pyrrolidine-5,5-trans-lactams, a series of inhibitors of the HCV NS3/4A protease. The absolute levels of processed, mature HCV nonstructural proteins in this system were found to decrease in the presence of the trans-lactams. Monitoring of this reduction enabled end points and 50% inhibitory concentrations to be calculated in order to rank the active compounds according to potency. These compounds had no effect on the transcription or translation of the NS3-5 polyprotein at concentrations shown to inhibit NS3/4A protease, and they were shown to be specific inhibitors of this protease. The ELISA, originally developed using the vaccinia virus expression system, was modified to utilize Huh-7 cells containing an HCV replicon. Results with this assay correlated well with those obtained with the recombinant vaccinia virus assays. These results demonstrate the utility of these assays for the characterization of NS3/4A protease inhibitors. In addition, inhibitors of other viral targets, such as polymerase and helicase, can be evaluated in the context of the replicon ELISA.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Lactamas/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Linhagem Celular , Chlorocebus aethiops , Ensaio de Imunoadsorção Enzimática , Hepacivirus/enzimologia , Humanos , Lactamas/química , Testes de Sensibilidade Microbiana/métodos , Replicon , Vaccinia virus/enzimologia , Vaccinia virus/genética , Células Vero , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
6.
Antimicrob Agents Chemother ; 48(12): 4542-9, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15561823

RESUMO

Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.


Assuntos
Antivirais/administração & dosagem , Antivirais/farmacologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/enzimologia , Animais , Antivirais/uso terapêutico , Linhagem Celular , Cromatografia em Gel , Efeito Citopatogênico Viral/efeitos dos fármacos , Cães , Inibidores Enzimáticos/uso terapêutico , Guanidinas , Indicadores e Reagentes , Cinética , Pulmão/metabolismo , Masculino , Camundongos , Microscopia Eletrônica , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/crescimento & desenvolvimento , Infecções por Orthomyxoviridae/prevenção & controle , Piranos , Ratos , Ratos Sprague-Dawley , Ácidos Siálicos/química , Ácidos Siálicos/farmacologia , Relação Estrutura-Atividade , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos , Zanamivir
8.
J Med Chem ; 46(21): 4428-49, 2003 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-14521407

RESUMO

A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/enzimologia , Lactamas/síntese química , Lactamas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Serina Endopeptidases/metabolismo , Animais , Antivirais/sangue , Disponibilidade Biológica , Encéfalo/metabolismo , Células Cultivadas , Cães , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática , Olho/metabolismo , Ganciclovir/farmacologia , Cobaias , Meia-Vida , Humanos , Indicadores e Reagentes , Cinética , Espectrometria de Massas , Modelos Moleculares , Inibidores de Proteases/sangue , Relação Estrutura-Atividade , Especificidade por Substrato
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