In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide.
J Am Chem Soc
; 135(31): 11623-11633, 2013 Aug 07.
Article
en En
| MEDLINE
| ID: mdl-23848581
ABSTRACT
The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum, and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteína p53 Supresora de Tumor
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Ciclotidas
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Antineoplásicos
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos