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Antiviral Res ; 156: 46-54, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29870771

RESUMO

Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2. One compound (MCCB4) was efficacious (EC50 4.8 µM), exhibited low cytotoxicity (CC50 > 100 µM) and was specific, with no effect on either a T7 RNA polymerase driven firefly luciferase or a Bunyamwera virus minigenome. Further investigations revealed that this small molecule inhibitor was able to outcompete established replication complexes, an essential aspect for a potential EBOV treatment.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Ebolavirus/genética , Transcrição Gênica/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Ebolavirus/fisiologia , Simulação de Dinâmica Molecular , Nucleoproteínas/metabolismo , Ligação Proteica , Proteínas Virais/metabolismo
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