The intracellular pharmacokinetics of terminally capped peptides.

@article{Ruttekolk2012TheIP,
  title={The intracellular pharmacokinetics of terminally capped peptides.},
  author={Ivo R. Ruttekolk and J. Witsenburg and Heike Glauner and P. Bovee-Geurts and E. Ferro and W. P. Verdurmen and R. Brock},
  journal={Molecular pharmaceutics},
  year={2012},
  volume={9 5},
  pages={
          1077-86
        }
}
With significant progress in delivery technologies, peptides and peptidomimetics are receiving increasing attention as potential therapeutics also for intracellular applications. However, analyses of the intracellular behavior of peptides are a challenge; therefore, knowledge on the intracellular pharmacokinetics of peptides is limited. So far, most research has focused on peptide degradation in the context of antigen processing, rather than on peptide stability. Here, we studied the structure… Expand
Identification of Short Hydrophobic Cell-Penetrating Peptides for Cytosolic Peptide Delivery by Rational Design.
TLDR
A design principle based on a classification of peptides according to accumulated side-chain polarity and hydrophobicity is demonstrated, showing that in comparison to randomly selected peptides, CPPs cover a distinct parameter space. Expand
Stabilization of peptides against proteolysis through disulfide-bridged conjugation with synthetic aromatics.
TLDR
This work developed a general, convenient, and efficient strategy for the stabilization of peptides against proteolysis, which involves noncovalent π-π interactions between aromatic amino acid residues in peptides and synthetic electron-deficient aromatics, together with the implication of steric hindrance (from the bulky NDI moiety), and the enhancement of peptide α-helicity. Expand
Exploration of the design principles of a cell-penetrating bicylic peptide scaffold.
TLDR
The results demonstrate that both arginine clustering and spatial constraints are uptake-promoting structural principles, an observation that gives freedom in the introduction of cell-penetrating capacity to structurally constrained scaffolds. Expand
Multivalent peptides displayed on OEGMA-based copolymers for the modulation of protein–protein interactions
Direct conjugation of peptides to large polymers has been a promising strategy to overcome the intrinsic limitation of peptides in terms of circulation lifetime, proteolytic stability, andExpand
Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction
TLDR
Results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage and because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides. Expand
Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by fluorescence correlation spectroscopy.
TLDR
The present results suggest that the diverse cellular uptake mechanisms, often reported for amphipathic CPPs, might result from the synergistic effect of peptide monomers, self-aggregates and cargo complexes, distributed unevenly at the plasma membrane. Expand
Cell surface clustering of heparan sulfate proteoglycans by amphipathic cell-penetrating peptides does not contribute to uptake.
TLDR
It is reported that various TP10 analogs differ in their capacity to accumulate on HS-rich plasma membranes in an HS-dependent manner and that there is no direct coupling of interaction, accumulation and uptake. Expand
Stabilization of peptides for intracellular applications by phosphoramidate-linked polyethylene glycol chains.
TLDR
It is shown that phosphoramidate-linked PEGylated proapoptotic peptides display a dramatically increased stability in Jurkat cell lysate and a homogenous intracellular distribution as well as high apoptotic activity after introduction into cells. Expand
The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides.
TLDR
A platform to enhance the proteolytic stability of peptides was developed by controllably dimerizing them into α-helical dimers, connected by two disulfide bonds, which appears promising for conveniently creating prodrugs composed entirely of the therapeutic peptide itself (i.e., in the form of a dimer). Expand
Potent retro-inverso D-peptide for simultaneous targeting of angiogenic blood vasculature and tumor cells.
TLDR
The data demonstrate that D-SP5 displays higher binding affinities toward tumor endothelium as well as tumor cells and enhanced tumor targeting capability in vitro and in vivo. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 37 REFERENCES
A doubly labeled penetratin analogue as a ratiometric sensor for intracellular proteolytic stability.
TLDR
Results indicate that cytoplasmic fluorescence, typically interpreted as CPP entering the cytosol, may originate from proteolytic breakdown products, and is likely to affect the intracellular integrity of the vector and the cargo. Expand
In vivo biodistribution and efficacy of peptide mediated delivery.
TLDR
Recent progress in the field has shown cell-penetrating peptides to be effective for in vivo delivery with retained biological activity of a wide variety of bioactive cargoes into virtually any mammalian tissue. Expand
The design, synthesis and application of stereochemical and directional peptide isomers: a critical review.
  • P. Fischer
  • Chemistry, Medicine
  • Current protein & peptide science
  • 2003
TLDR
The actual structural implications of modifying amino acid stereochemistry and peptide bond direction are reviewed critically here and the reasons for the lack of general success with this strategy are discussed. Expand
Measurements of the intracellular stability of CPPs.
TLDR
Fluorescence correlation spectroscopy (FCS) is introduced as a powerful method to address peptide stability in cells and cell lysates and provides direct information on peptide degradation and association with cellular structures in intact cells. Expand
Analysis of Intracellular Substrates and Products of Thimet Oligopeptidase in Human Embryonic Kidney 293 Cells*
TLDR
Over 100 peptides in human embryonic kidney 293 (HEK293) cells that are derived from intracellular proteins are identified, supporting the proposal that EP24.15 can function in the degradation of peptides that could be used for antigen presentation and the potential candidates to regulate protein interactions within cells. Expand
Peptidomic analysis of human cell lines.
TLDR
Quantitative peptidomic analysis indicated that the levels of most cellular peptides are not altered in response to elevated intracellular calcium, suggesting that calpain is not responsible for their production. Expand
A Targeted Protease Substrate for a Quantitative Determination of Protease Activities in the Endolysosomal Pathway
TLDR
A fluorescence resonance energy transfer‐based probe and protocols are presented for a quantitative determination of proteolytic activities inside the endolysosomal compartment and it is demonstrated that only a minor fraction of the peptide reaches the cytoplasm in its intact form. Expand
A quantitative validation of fluorophore-labelled cell-permeable peptide conjugates: fluorophore and cargo dependence of import.
TLDR
In spite of the very different physicochemical characteristics of the fluorophores, the import efficiencies for analogues labelled at different positions within the sequence of the import peptides showed a strong positive correlation. Expand
Terminal modifications inhibit proteolytic degradation of an immunogenic mart‐127–35 peptide: Implications for peptide vaccines
TLDR
Evaluated the stability of the immunogenic peptide MART‐127–35 in fresh normal human plasma (NHP) and modified forms of that peptide for stability and immune recognition in an in vitro model and identified modifications that convey protection against enzymatic destruction without loss of immunogenicity. Expand
Intracellular Peptides as Natural Regulators of Cell Signaling*
TLDR
The results suggest that before their complete degradation, intracellular peptides similar to those generated by proteasomes can actively affect cell signaling, probably representing additional bioactive molecules within cells. Expand
...
1
2
3
4
...