Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction.
J Clin Invest
; 115(2): 379-87, 2005 Feb.
Article
em En
| MEDLINE
| ID: mdl-15690085
ABSTRACT
The EGF-like domain of smallpox growth factor (SPGF) targets human ErbB-1, inducing tyrosine phosphorylation of certain host cellular substrates via activation of the receptor's kinase domain and thereby facilitating viral replication. Given these findings, low molecular weight organic inhibitors of ErbB-1 kinases might function as antiviral agents against smallpox. Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization. Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading. In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection. Collectively, these findings show that chemical inhibitors of host-signaling pathways exploited by viral pathogens may represent potent antiviral therapies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Vírus da Varíola
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Proteínas Virais
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Varíola
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Transdução de Sinais
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Morfolinas
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Substâncias de Crescimento
/
Receptores ErbB
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article