Induction of caspase-8 in human cells by the extracellular administration of peptides containing a C-terminal SLV sequence

Scheller, Anne; Melzig, Matthias F.; Oehlke, J.

doi:10.1007/bf02443575

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…Externally administered KLA-peptide bearing the tripeptide SLV Cterminally is able to specifically activate caspase 8. The specificity is indicated by the inactivity of the components alone and of the KLA-conjugate bearing the SLV-sequence N-terminally (Scheller et al, 2001). Replacement of the KLA-peptide by the Antennapedia sequence resulted in similar biological activity.…”

Section: Substance P Rapidly Translocates Through the Plasma Membranementioning

confidence: 99%

Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides

Oehlke¹,

Lorenz²,

Wiesner³

et al. 2005

J. Mol. Recognit.

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In the last decade many peptides have been shown to be internalized into various cell types by different, poorly characterized mechanisms. This review focuses on uptake studies with substance P (SP) aimed at unravelling the mechanism of peptide-induced mast cell degranulation, and on the characterization of the cellular uptake of designed KLA-derived model peptides. Studies on structure-activity relationships and receptor autoradiography failed to detect specific peptide receptors for the undecapeptide SP on mast cells. In view of these findings, a direct interaction of cationic peptides with heterotrimeric G proteins without the participation of a receptor has been proposed. Such a process would require insertion into and translocation of peptides across the plasma membrane. In order to clarify whether a transport of cationic peptides into rat peritoneal mast cells is possible, transport studies were performed by confocal laser scanning microscopy (CLSM) using fluorescence-labeled Arg(3),Orn(7)-SP and its D-amino acid analog, all-D-Arg(3),Orn(7)-SP, as well as by electron microscopic autoradiography using (3)H-labelled SP and (125)I-labelled all-D-SP. The results obtained by CLSM directly showed translocation of SP peptides into pertussis toxin-treated cells. Kinetic experiments indicated that the translocation process was rapid, occurring within a few seconds. Mast cell degranulation induced by analog of magainin 2 amide, neuropeptide Y and the model peptide acetyl-KLALKLALKALKAALKLA-amide was also found to be very fast, pointing to an extensive translocation of the peptides. In order to learn more about structural requirements for the cellular uptake of peptides, the translocation behavior of a set of systematically modified KLA-based model peptides has been studied in detail. By two different protocols for determining the amount of internalized peptide, evidence was found that the structure of the peptides only marginally affects their uptake, whereas the efflux of cationic, amphipathic peptides is strikingly diminished, thus allowing their enrichment within the cells. Although the mechanism of cellular uptake, consisting of energy-dependent and -independent contributions, is not well understood, KLA-derived peptides have been shown to deliver various cargos (PNAs, peptides) into cells. The results obtained with SP- and KLA-derived peptides are discussed in the context of the current literature.

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Section: Substance P Rapidly Translocates Through the Plasma Membranementioning

confidence: 99%

Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides

Oehlke¹,

Lorenz²,

Wiesner³

et al. 2005

J. Mol. Recognit.

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“…MAP (named after “model amphipathic peptide”) is an artificial CPP that integrates both hydrophobic and hydrophilic residues in opposite sides of its α-helical structure, resulting in a very well-defined amphipathic α-helix [ 13 ]. This CPP, whose sequence is KLALKLALKALKAALKLA, has the ability to translocate a variety of compounds such as oligonucleotides [ 14 ], peptides [ 15 ], and small proteins (like cytochrome c) across cell membranes [ 16 ]. Moreover, in a study by Hällbrink et al, addressing the cellular uptake kinetics of several CPP, MAP was found to display the fastest cellular uptake, along with the ability to induce leakage by disturbing the membrane integrity at concentrations as low as 1 μM [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

Silva

Alves

Duarte

et al. 2020

IJMS

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Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.

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“…Replacement of the KLA-peptide by penetratin resulted in similar biological activity. 240 In a comparative study Hällbrink et al have demonstrated that peptide KLALKLALKALKAALKLA and its conjugate with a model pentapeptide cargo are taken up more efficiently and quickly by Bowes human melanoma cells than similar pentamer construct of other cell penetrating peptides like transportan, Tat (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60), or penetratin. 75 The uptake of antisense ODNs by mammalian cells (calf aortic endothelial cells, CHO cells) was compared with that of their respective conjugates or complexes with cationic KLA peptides (KLALKLALKALKAALKLA, KALKLKLAALALLKLKLA, KLGLKLGLKGLKGGLKLG, KGLKLKGGLGLLGKLKLG) of varying helix-forming propensity and amphipathicity and with penetratin.…”

Section: Kla Model Peptidesmentioning

confidence: 99%

Medium‐sized peptides as built in carriers for biologically active compounds

Hudecz

Bánóczi

Csı́k

2005

Medicinal Research Reviews

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A growing number of oligopeptides of natural and/or synthetic origin have been described and considered as targeting structures for delivery bioactive compounds into various cell types. This review will outline the discovery of peptide sequences and the corresponding mid-sized oligopeptides with membrane translocating properties and also summarize de novo designed structures possessing similar features. Conjugates and chimera constructs derived from these sequences with covalently attached bioactive peptide, epitope, oligonucleotide, PNA, drug, reporter molecule will be reviewed. A brief note will refer to the present understanding on the uptake mechanism at the end of each section.

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Induction of caspase-8 in human cells by the extracellular administration of peptides containing a C-terminal SLV sequence

Cited by 4 publications

References 31 publications

Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides

Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides

Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

Medium‐sized peptides as built in carriers for biologically active compounds

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