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In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide.
Ji, Yanbin; Majumder, Subhabrata; Millard, Melissa; Borra, Radhika; Bi, Tao; Elnagar, Ahmed Y; Neamati, Nouri; Shekhtman, Alexander; Camarero, Julio A.
Afiliação
  • Ji Y; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Majumder S; Department of Chemistry, State University of New York, Albany, NY 12222, USA.
  • Millard M; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Borra R; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Bi T; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Elnagar AY; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Neamati N; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
  • Shekhtman A; Department of Chemistry, State University of New York, Albany, NY 12222, USA.
  • Camarero JA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
J Am Chem Soc ; 135(31): 11623-11633, 2013 Aug 07.
Article em En | MEDLINE | ID: mdl-23848581
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteína Supressora de Tumor p53 / Ciclotídeos / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteína Supressora de Tumor p53 / Ciclotídeos / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article