Article

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

Journal of the American Chemical Society (Impact Factor: 12.11). 07/2013; 135(31). DOI: 10.1021/ja405108p
Source: PubMed

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.

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Available from: Yanbin Ji, Oct 16, 2014
    • "For instance, MCoTI-II seems to be internalized by multiple endocytic pathways, but in particular by macropinocytosis (Cascales et al., 2011). We are unsure whether and how MCoTI-I/II peptides escape endosomes, but the fact that this peptide when grafted with a functional segment of p53 can inhibit the interaction of the oncogenic protein HdmX with p53, both located in the cytoplasm, suggests that the grafted peptide and/or an active metabolite is also active in the cytoplasm (Ji et al., 2013). kB1 seems to be able to target PErich membranes and to enter through endocytosis, but also to translocate through the plasma membrane in a soluble form. "
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    ABSTRACT: Cyclotides combine the stability of disulfide-rich peptides with the intracellular accessibility of cell-penetrating peptides, giving them outstanding potential as drug scaffolds with an ability to inhibit intracellular protein-protein interactions. To realize and optimize the application of cyclotides as a drug framework and delivery system, we studied the ability of the prototypic cyclotide, kalata B1, to enter mammalian cells. We show that kalata B1 can enter cells via both endocytosis and direct membrane translocation. Both pathways are initiated by targeting phosphatidylethanolamine phospholipids at the cell surface and inducing membrane curvature. This unusual approach to initiate internalization might be harnessed to deliver drugs into cells and, in particular, cancer cells, which present a higher proportion of surface-exposed phosphatidylethanolamine phospholipids. Our findings highlight the potential of these peptides as drug leads for the modulation of traditionally "undruggable" targets, such as intracellular protein-protein interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · Chemistry & biology
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    • "Several small molecules have been so far reported as p53-pathway modulators [17].The capability of 5- deazaflavin derivatives to activate the tumor suppressor p53 in cancer cells was reported through inhibition of the p53-specific ubiquitin E3 ligase HDM2 (Chart 1) [18e20]. In addition, some diphenylimidazolidines, glucocorticoids and engineered cyclotides have been reported to play the same role [21] [22]. "
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    ABSTRACT: Cellular tumor antigen p53 is crucial for cancer prevention via different mechanisms. E3 ubiquitin-protein ligase HDM2 binds to p53, blocks its ability to activate transcription, and therefore acts as a negative regulator. Blocking p53 binding site on HDM2 was believed to generate efficient antitumor agents. So far, limited scaffolds were reported with HDM2 antagonist activity. Herein, diphenylpyrroles were introduced and evaluated as a novel scaffold in the field of p53 activators. An efficient synthesis of novel 3-heteroaryl-pyrroles is described via reactions of E-3-(dimethylamino)-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)prop-2-en-1-one or E-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)-3-morpholinoprop-2-en-1-one with hydrazine hydrate, phenyl hydrazine, hydroxylamine, various heterocyclic amines and active methylene compounds.
    Full-text · Article · Jun 2014 · European Journal of Medicinal Chemistry
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    • "Several small molecules have been so far reported as p53-pathway modulators [17].The capability of 5- deazaflavin derivatives to activate the tumor suppressor p53 in cancer cells was reported through inhibition of the p53-specific ubiquitin E3 ligase HDM2 (Chart 1) [18e20]. In addition, some diphenylimidazolidines, glucocorticoids and engineered cyclotides have been reported to play the same role [21] [22]. "
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    ABSTRACT: An efficient synthesis of novel 4,5-diphenyl-3-heteroaryl-pyrroles were synthesized and evaluated as a novel scaffold in the field of p53 activators.
    Full-text · Article · Jan 2014
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