Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.
J Med Chem
; 62(12): 5810-5831, 2019 06 27.
Article
en En
| MEDLINE
| ID: mdl-31136173
ABSTRACT
There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Antivirales
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Piridinas
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Proteínas Serina-Treonina Quinasas
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Inhibidores de Proteínas Quinasas
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2019
Tipo del documento:
Article