Cell‐Penetrating Homochiral Cyclic Peptides as Nuclear‐Targeting Molecular Transporters

Mandal, Deendayal; Shirazi, Amir Nasrolahi; Parang, Keykavous

doi:10.1002/ange.201102572

Cited by 46 publications

(101 citation statements)

References 19 publications

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“…This work, along with two other recent reports, 28,29 demonstrates that cyclization of Arg-rich CPPs enhances their membrane permeability. Our results further reveal that a proper combination of peptide sequence and ring size is critical for efficient cellular uptake.…”

Section: Resultssupporting

confidence: 83%

Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs

et al. 2012

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Cyclic peptides hold great potential as therapeutic agents and research tools, but their broad application has been limited by poor membrane permeability. Here, we report a potentially general approach for intracellular delivery of cyclic peptides. Short peptide motifs rich in arginine and hydrophobic residues (e.g., FΦRRRR, where Φ is L-2-naphthylalanine), when embedded into small- to medium-sized cyclic peptides (7–13 amino acids), bound to the plasma membrane of mammalian cultured cells and were subsequently internalized by the cells. Confocal microscopy and a newly developed peptide internalization assay demonstrated that cyclic peptides containing these transporter motifs were translocated into the cytoplasm and nucleus at efficiencies 2–5-fold higher than that of nonaarginine (R9). Furthermore, incorporation of the FΦRRRR motif into a cyclic peptide containing a phosphocoumaryl aminopropionic acid (pCAP) residue generated a cell permeable, fluorogenic probe for detecting intracellular protein tyrosine phosphatase activities.

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Section: Resultssupporting

confidence: 83%

Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs

et al. 2012

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“…Cyclic peptide RGDfK (cRGD) and non-specific control cyclic peptide RADfK (cRAD) were synthesized using standard solid phase peptide chemistry from Fmoc-protected amino acids on a 2-chlorotrityl chloride resin followed by cleavage, cyclization and deprotection. (27, 28)…”

Section: Methodsmentioning

confidence: 99%

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

2016

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The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane–modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging.

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“…31 This system showed that the optimized balance between positive charge and hydrophobicity was critical for the peptide to enhance the intracellular delivery of drugs through interaction with the cell membrane and penetration into the lipid bilayer. Cyclic [WR] 4 provided major advantages compared to their linear counterparts, including higher enzymatic stability, bypassing endosomal uptake, improved cell permeability, and nuclear targeting.…”

Section: Introductionmentioning

confidence: 99%

“…Cyclic [WR] 4 provided major advantages compared to their linear counterparts, including higher enzymatic stability, bypassing endosomal uptake, improved cell permeability, and nuclear targeting. 31 …”

Section: Introductionmentioning

confidence: 99%

Efficient Delivery of Cell Impermeable Phosphopeptides by a Cyclic Peptide Amphiphile Containing Tryptophan and Arginine

Shirazi

Tiwari

et al. 2013

Mol. Pharmaceutics

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Phosphopeptides are valuable reagent probes for studying protein-protein and protein-ligand interactions. The cellular delivery of phosphopeptides is challenging because of the presence of the negatively charged phosphate group. The cellular uptake of a number of fluorescent-labeled phosphopeptides, including F′-GpYLPQTV, F′-NEpYTARQ, F′-AEEEIYGEFEAKKKK, F′-PEpYLGLD, F′-pYVNVQN-NH2, and F′-GpYEEI (F′ = fluorescein) was evaluated in the presence or absence of a [WR]4, a cyclic peptide containing alternative arginine (R) and tryptophan (W) residues, in human leukemia cells (CCRF-CEM) after 2 h incubation using flow cytometry. [WR]4 improved significantly the cellular uptake of all phosphopeptides. PEpYLGLD is a sequence that mimics the pTyr1246 of ErbB2 that is responsible for binding to the Chk SH2 domain. The cellular uptake of F′-PEpYLGLD was enhanced dramatically by 27-fold in the presence of [WR]4 and was found to be time-dependent. Confocal microscopy of a mixture of F′-PEpYLGLD and [WR]4 in live cells exhibited intracellular localization and significantly higher cellular uptake compared to that of F′-PEpYLGLD alone. Transmission Electron Microscopy (TEM) and Isothermal Calorimetric (ITC) were used to study the interaction of PEpYLGLD and [WR]4. TEM results showed that the mixture of PEpYLGLD and [WR]4 formed noncircular nanosized structures with width and height of 125 and 60 nm, respectively. ITC binding studies confirmed the interaction between [WR]4 and PEpYLGLD. The binding isotherm curves, derived from sequential binding models, showed an exothermic interaction driven by entropy. These studies suggest that amphiphilic peptide [WR]4 can be used as a cellular delivery tool of cell-impermeable negatively charged phosphopeptides.

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Cell‐Penetrating Homochiral Cyclic Peptides as Nuclear‐Targeting Molecular Transporters

Cited by 46 publications

References 19 publications

Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs

Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

Efficient Delivery of Cell Impermeable Phosphopeptides by a Cyclic Peptide Amphiphile Containing Tryptophan and Arginine

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