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1.
J Med Chem ; 59(10): 4563-77, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27095056

RESUMO

People throughout the world continue to be at risk for death from influenza A virus, which is always creating a new variant. Here we present a new effective and specific anti-influenza viral neuraminidase (viNA) inhibitor, 9-cyclopropylcarbonylamino-4-guanidino-Neu5Ac2en (cPro-GUN). Like zanamivir, it is highly effective against N1-N9 avian and N1-N2 human viNAs, including H274Y oseltamivir-resistant N1 viNA, due to its C-6 portion still being anchored in the active site, different from the disruption of oseltamivir's C-6 anchoring by H274Y mutation. Unlike zanamivir, no sialidase inhibitory activity has been observed for cPro-GUN against huNeu1-huNeu4 enzymes. Broad efficacy of cPro-GUN against avian and human influenza viruses in cell cultures comparable to its sialidase inhibitory activities makes cPro-GUN ideal for further development for safe therapeutic or prophylactic use against both seasonal and pandemic influenza.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Galinhas , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Células Madin Darby de Rim Canino , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Neuraminidase/metabolismo , Orthomyxoviridae/crescimento & desenvolvimento , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
2.
Biochem Biophys Res Commun ; 459(2): 288-293, 2015 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-25727021

RESUMO

Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs.


Assuntos
Biflavonoides/farmacologia , Cacau/química , Catequina/farmacologia , HIV-1/efeitos dos fármacos , Proantocianidinas/farmacologia , Provírus/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Biflavonoides/química , Biflavonoides/isolamento & purificação , Catequina/química , Catequina/isolamento & purificação , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Indóis/farmacologia , Células Jurkat , Sistema de Sinalização das MAP Quinases , Maleimidas/farmacologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , NF-kappa B/metabolismo , Fitoterapia , Plantas Medicinais/química , Proantocianidinas/química , Proantocianidinas/isolamento & purificação , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Provírus/fisiologia , Latência Viral/efeitos dos fármacos
3.
FEBS Open Bio ; 3: 231-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23772399

RESUMO

In a comparison of sialidase activities toward N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), we found that Salmonella typhimurium LT2 sialidase (STSA) hardly cleaved 4-methylumbelliferyl Neu5Gc (4MU-Neu5Gc). The k cat/K m value of STSA for 4MU-Neu5Gc was found to be 110 times lower than that for 4-methylumbelliferyl Neu5Ac (4MU-Neu5Ac). Additionally, STSA had remarkably weak ability to cleave α2-3-linked-Neu5Gc contained in gangliosides and equine erythrocytes. In silico analysis based on first-principle calculations with transition-state analogues suggested that the binding affinity of Neu5Gc2en is 14.3 kcal/mol more unstable than that of Neu5Ac2en. The results indicated that STSA preferentially cleaves Neu5Ac residues rather than Neu5Gc residues, which is important for anyone using this enzyme to cleave α2-3-linked sialic acids.

4.
J Virol ; 87(13): 7726-36, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23658440

RESUMO

Since HIV-1 replication is modulated at multiple stages by host cell factors, identification and characterization of those host cell factors are expected to contribute to the development of novel anti-HIV therapeutics. Previous studies showed that a C-terminally truncated cytosolic form of cleavage and polyadenylation-specific factor 6 (CPSF6-358) inhibits HIV-1 infection through interference with HIV-1 trafficking to the nucleus. Here we identified and characterized a different configuration of C-terminally truncated human CPSF6 (hCPSF6-375) through cDNA expression cloning coupled with ganciclovir-mediated lethal selection. Notably, hCPSF6-375, but not mouse CPSF6-358 (mCPSF6-358) as previously reported, remarkably interfered with viral cDNA synthesis after HIV-1 infection. Moreover, we found that hCPSF6-375 aberrantly accelerated the disassembly of the viral capsid in target cells, while CPSF6-358 did not. Sequence comparison of CPSF6-375 and CPSF6-358 cDNAs showed a lack of exon 6 and additional coding sequence for 54 amino acid residues in the C terminus of hCPSF6-375. Mutational analyses revealed that the residues encoded by exon 6, but not the C-terminal 54 residues in hCPSF6-375, is responsible for impaired viral cDNA synthesis by hCPSF6-375. This is the first report demonstrating a novel mode of HIV-1 inhibition by truncated forms of CPSF6 that involves rapid capsid disassembly and inhibition of viral cDNA synthesis. These findings could facilitate an increased understanding of viral cDNA synthesis in light of the viral capsid disassembly.


Assuntos
Capsídeo/metabolismo , DNA Complementar/biossíntese , HIV-1/genética , Replicação Viral/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Fator de Especificidade de Clivagem e Poliadenilação/genética , Análise Mutacional de DNA , Vetores Genéticos/genética , Células HEK293 , HIV-1/fisiologia , Células HeLa , Humanos , Camundongos , Dados de Sequência Molecular , Replicação Viral/fisiologia
5.
J Invertebr Pathol ; 112(1): 102-4, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23026703

RESUMO

Differences in the viral susceptibility of multiple insect hemocyte morphotypes have not been investigated to date. In this study, a Bombyx mori nucleopolyhedrovirus (BmNPV) derivative possessing a Drosophila hsp70 promoter-driven green fluorescent protein (GFP) gene was used to observe NPV tropism of B. mori larval hemocytes. The experiments clearly revealed that there were fewer GFP-positive plasmatocytes than those observed in other types of hemocytes, such as granulocytes, oenocytoids, and spherulocytes, when infected via the intrahemocoelic or oral route. Our results indicate that silkworm plasmatocytes are more resistant than other hemocyte morphotypes to BmNPV infection.


Assuntos
Bombyx/virologia , Hemócitos/virologia , Nucleopoliedrovírus/patogenicidade , Animais
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