Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1

D’Souza, Charlotte; Henriques, Sónia Troeira; Wang, Conan K.; Craik, David J.

doi:10.1016/j.ejmech.2014.06.047

Cited by 51 publications

(61 citation statements)

References 50 publications

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“…TAT was included as a positive control, and its derivative TAT-G (in which positively charged residues are replaced with Gly) (D'Souza et al, 2014), was included as a negative control to evaluate non-specific cellular internalization. As each peptide is labeled with Alexa Fluor 488 and its fluorescence emission quantum yield is insensitive to environment (Gadd et al, 2012), the mean fluorescence emission signal is directly proportional to the amount of peptide internalized into cells, whereas the percentage of fluorescent cells represents the fraction of cells that have internalized the peptide.…”

Section: Internalization Of Labeled Kb1 Analogsmentioning

confidence: 99%

“…The linear peptides were synthesized using an automated peptide synthesizer (Symphony peptide synthesizer, Protein Technologies) as described previously (D'Souza et al, 2014).…”

Section: Peptide Extraction and Synthesismentioning

confidence: 99%

“…Internalization of labeled peptides was evaluated using a BD FACSCanto II flow cytometer, as described previously (D'Souza et al, 2014;Torcato et al, 2013).…”

Section: Internalization Of Kb1 Into Cells Followed By Flow Cytometrymentioning

confidence: 99%

“…The intracellular uptake of cyclotides belonging to the trypsin inhibitor subfamily (i.e. MCoTI-I and MCoTI-II) is reported to be dependent on endocytic routes (Cascales et al, 2011;Contreras et al, 2011;Greenwood et al, 2007) and independent of insertion into the plasma membrane (Cascales et al, 2011;D'Souza et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

Henriques

Huang

Chaousis

et al. 2015

Chemistry & Biology

108

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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.

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Section: Internalization Of Labeled Kb1 Analogsmentioning

confidence: 99%

“…The linear peptides were synthesized using an automated peptide synthesizer (Symphony peptide synthesizer, Protein Technologies) as described previously (D'Souza et al, 2014).…”

Section: Peptide Extraction and Synthesismentioning

confidence: 99%

“…Internalization of labeled peptides was evaluated using a BD FACSCanto II flow cytometer, as described previously (D'Souza et al, 2014;Torcato et al, 2013).…”

Section: Internalization Of Kb1 Into Cells Followed By Flow Cytometrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

Henriques

Huang

Chaousis

et al. 2015

Chemistry & Biology

108

View full text Add to dashboard Cite

show abstract

“…Cyclotides have been also engineered to target extracellular [10–12] and intracellular [13] molecular targets in animal models. Some of these novel cyclotides have been shown to be orally bioavailable [11] and able to efficiently cross cellular-membranes [14–16]. Altogether, these features make the cyclotide scaffold an excellent molecular framework for the design of novel peptide-based therapeutics [2, 17].…”

Section: Introductionmentioning

confidence: 99%

Rapid Parallel Synthesis of Bioactive Folded Cyclotides by Using a Tea‐Bag Approach

et al. 2015

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We report here for the first time the rapid parallel production of bioactive folded cyclotides by using Fmoc-based solid-phase peptide synthesis in combination with a tea-bag approach. Using this approach we efficiently synthesized 15 different analogs of the CXCR4 antagonist cyclotide MCo-CVX-5c. Cyclotides were cyclized using a single-pot cyclization/folding reaction in the presence of reduced glutathione. Natively folded cyclotides were quickly purified from the cyclization/folding crude by activated thiol sepharose-based chromatography. The different folded cyclotide analogs were finally tested for their ability to inhibit the CXCR4 receptor in a cell-based assay. These results indicate that this approach can be used for the efficient chemical synthesis of cyclotide-based libraries that can be easily interfaced with solution or cell-based assays for the rapid screening of novel cyclotides with improved biological properties.

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Bioactive and Membrane‐Permeable Cyclic Peptide Natural Products

Bockus¹,

Lokey

2017

Practical Medicinal Chemistry With Macrocycles

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Structural parameters modulating the cellular uptake of disulfide-rich cyclic cell-penetrating peptides: MCoTI-II and SFTI-1

Cited by 51 publications

References 50 publications

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

The Prototypic Cyclotide Kalata B1 Has a Unique Mechanism of Entering Cells

Rapid Parallel Synthesis of Bioactive Folded Cyclotides by Using a Tea‐Bag Approach

Bioactive and Membrane‐Permeable Cyclic Peptide Natural Products

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