Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library.
J Virol
; 86(5): 2632-40, 2012 Mar.
Article
en En
| MEDLINE
| ID: mdl-22205744
ABSTRACT
Orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox virus, and the potential biothreat variola virus (the causative agent of smallpox). There is currently no FDA-approved drug for humans infected with orthopoxviruses. We screened a diversity-oriented synthesis library for new scaffolds with activity against vaccinia virus. This screen identified a nonnucleoside analog that blocked postreplicative intermediate and late gene expression. Viral genome replication was unaffected, and inhibition could be elicited late in infection and persisted upon drug removal. Sequencing of drug-resistant viruses revealed mutations predicted to be on the periphery of the highly conserved viral RNA polymerase large subunit. Consistent with this, the compound had broad-spectrum activity against orthopoxviruses in vitro. These findings indicate that novel chemical synthesis approaches are a potential source for new infectious disease therapeutics and identify a potentially promising candidate for development to treat orthopoxvirus-infected individuals.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Pirimidinonas
/
Orthopoxvirus
/
Evaluación Preclínica de Medicamentos
/
Bibliotecas de Moléculas Pequeñas
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Virol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos