In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide

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• 作者：Yanbin Ji ; Subhabrata Majumder ; Melissa Millard ; Radhika Borra ; Tao Bi ; Ahmed Y. Elnagar ; Nouri Neamati ; Alexander Shekhtman ; Julio A. Camarero
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：August 7, 2013
• 年：2013
• 卷：135
• 期：31
• 页码：11623-11633
• 全文大小：672K
• 年卷期：v.135,no.31(August 7, 2013)
• ISSN：1520-5126

文摘

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鈥損rotein interactions.