A mitochondrial targeted fusion peptide exhibits remarkable cytotoxicity

Law, Benedict; Quinti, Luisa; Choi, Yongdoo; Weissleder, Ralph; Tung, Ching–Hsuan

doi:10.1158/1535-7163.mct-05-0509

Cited by 111 publications

(93 citation statements)

References 19 publications

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“…[21][22][23][24][25] In previous work, we took advantage of the integrin-clustering capacity of a tetravalent cRGD-containing peptide 26 to generate more effective antagonists with augmented specificity for tumors, [27][28][29][30] improved cellular uptake, 31,32 and enhanced toxicity upon association with proapoptotic peptides. 33,34 The tumor-targeted delivery of cytotoxic peptides (e.g., [KLAKLAK] 2 ) was initially of interest for the treatment of tumors, [35][36][37][38] particularly melanoma, when targeted by cRGD 39 or with a cell-penetrating peptide, such as TAT. 40 However, despite promising results, no follow-up studies have been reported on these compounds, certainly because of the modest activity of (KLAKLAK) 2 .…”

Section: Introductionmentioning

confidence: 99%

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

et al. 2017

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Melanoma is a highly metastatic and deadly form of cancer. Invasive melanoma cells overexpress integrin a v b 3 , which is a well-known target for Arg-Gly-Asp-based (RGD) peptides. We developed a sophisticated method to synthetize milligram amounts of a targeted vector that allows the RGD-mediated targeting, internalization, and release of a mitochondria-disruptive peptide derived from the pro-apoptotic Bax protein. We found that 2.5 mM Bax[109-127] was sufficient to destabilize the mitochondria in ten different tumor cell lines, even in the presence of the anti-apoptotic Bcl2 protein, which is often involved in tumor resistance. This pore-forming peptide displayed antitumor activity when it was covalently linked by a disulfide bridge to the tetrameric RAFT-c[RGD] 4 -platform and after intravenous injection in a human melanoma tumor model established in humanized immuno-competent mice. In addition to its direct toxic effect, treatment with this combination induced the release of the immuno-stimulating factor monocyte chimoattractant protein 1 (MCP1) in the blood and a decrease in the level of the pro-angiogenic factor FGF2. Our novel multifunctional, apoptosis-inducing agent could be further customized and assayed for potential use in tumortargeted therapy.

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Section: Introductionmentioning

confidence: 99%

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

et al. 2017

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“…As we know, kla cannot easily penetrate through the cell membrane, r7 as a delivery vector can increase the membrane-crossing ability of kla. Thus, the hybrid peptide of r7-kla showed stronger cellular uptake rate and stability due to the resistant ability to protease digestion and resulted to more cells apoptosis [45].…”

Section: Hybridizationmentioning

confidence: 99%

Design and Modification of Anticancer Peptides

Hu¹,

Chen²,

Zhao³

et al. 2016

Drug Des

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Cancer is a great concern in the public health and development of novel therapeutic agent or strategy become urgently. Anticancer peptides (ACPs) have become promising anticancer drug candidate molecules due to their several extraordinary properties, such as small size, high activity, low immunogenicity, good biocompatibility, diversity of sequence and more modification sites for the functional molecules. However, the low stability and short half-life of peptides are the major barriers for the application. In this review, we focus on the methods of peptide design and modification to improve the stability, half-life time and specificity of ACPs, which including amino acid substitution, cyclization, hybridization, fragmentization, modification of C-and N-terminal of peptide by polymer or targeting molecules, etc.modification of C-and N-terminal of peptide by polymer or targeting molecules, etc. The schematic diagram of major design and modification strategies of ACPs are shown in Figure 1.

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“…Penetratin, (R6/W3), and the glycosylated CPPs (at 50 μM; data not shown) and the KLAK cargo 31 did not decrease the number of viable cells even at 50 μM, the highest concentration which was used. It has been previously demonstrated with other KLAK analogs or with other cell lines that KLAK peptides are unable to cross the bilayer of eukaryotic cells unless they are coupled to a CPP [31] or a scaffold [32], which shuttle KLAK inside cells. The extent of cell death induced by all of the CPP-KLAK conjugates tested herein is reported in Fig.…”

Section: Cell Viability Studiesmentioning

confidence: 99%

“…According to the strategy depicted in Scheme 1, we have synthesized glycosylated analogs of (R6/W3), in which galactose unit(s) linked via click chemistry replace(s) one, two, or the three tryptophans. We have subsequently analyzed the viability of CHO cells treated by conjugates with the proapoptotic peptide KLAK, [31][32][33] and have visualized their localizations in these cells by fluorescence.…”

Section: Introductionmentioning

confidence: 99%

Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

et al. 2009

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Cell-penetrating peptides (CPPs), which are usually short basic peptides, are able to cross cell membranes and convey bioactive cargoes inside cells. CPPs have been widely used to deliver inside cells peptides, proteins, and oligonucleotides; however, their entry mechanisms still remain controversial. A major problem concerning CPPs remains their lack of selectivity to target a specific type of cell and/or an intracellular component. We have previously shown that myristoylation of one of these CPPs affected the intracellular distribution of the cargo. We report here on the synthesis of glycosylated analogs of the cell-penetrating peptide (R6/W3): Ac-RRWWRRWRR-NH 2 . One, two, or three galactose(s), with or without a spacer, were introduced into the sequence of this nonapeptide via a triazole link, the Huisgen reaction being achieved on a solid support. Four of these glycosylated CPPs were coupled via a disulfide bridge to the proapoptotic KLAK peptide, (KLAKLAKKLAKLAK), which alone does not enter into cells. The effect on cell viability and the uptake efficiency of different glycosylated conjugates were studied on CHO cells and were compared to those of the nonglycosylated conjugates: (R6/W3)S-S-KLAK and penetratinS-S-KLAK. We show that glycosylation significantly increases the cell viability of CHO cells compared to the nonglycosylated conjugates and concomitantly decreases the internalization of the KLAK cargo. These results suggest that glycosylation of CPP may be a key point in targeting specific cells.

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A mitochondrial targeted fusion peptide exhibits remarkable cytotoxicity

Cited by 111 publications

References 19 publications

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

Design and Modification of Anticancer Peptides

Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

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