Cell-penetrating Peptides Split into Two Groups Based on Modulation of Intracellular Calcium Concentration

Lorents, Annely; Kodavali, Praveen Kumar; Oskolkov, Nikita; Langel, Ülo; Hällbrink, Mattias; Pooga, Margus

doi:10.1074/jbc.m111.318063

Cited by 40 publications

(45 citation statements)

References 45 publications

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“…However, until we completed the studies described herein, it was unknown whether other CPPs could be used to deliver payloads to RBL-2H3 in a relatively inert fashion. This was an important question given that some CPPs, specifically those which elevate [Ca 2+ ] i , can trigger lysosomal exocytosis from cells such as the HeLa lines that are considered non-secretory [30]. In concordance with our results, the Tat CPP has no influence upon β-hexosaminidase release from HeLa cells even at a concentration of 20 μM [30].…”

Section: Discussionsupporting

confidence: 92%

“…Our data also identify C105Y as a very promising CPP that could be employed to deliver cargoes into MCs without promoting exocytosis [19]. Indeed, comparative investigations in spermatozoa [30] have also identified C105Y as a highly efficient CPP despite a relatively modest cationic charge density. Clearly, rationally-designed bioportides could also be employed both to decipher and modulate the exocytotic mechanisms of MCs that are fundamental to their multiple roles in acquired and innate immunity.…”

Section: Discussionmentioning

confidence: 58%

“…MP, MitP and TP10 interact with intracellular protein targets, most likely heterotrimeric G proteins of the G i subtype [10][11][12]31], and secretory responses to these peptides are only partially attenuated by the addition of EGTA to reduce [Ca 2+ ] o . In contract, the secretory actions of penetratin, Cyt c 77-101 and camptide are clearly dependent upon [Ca 2+ ] o and probably the consequence of a generalised Ca 2+ -influx in response to plasma membrane perturbation [30,32]. The secretory activity of camptide, a bioportide known to activate G proteins and elevate the second messenger cyclic adenosine monophosphate [6], can be explained by a selective activation of G s rather than G i .…”

Section: Discussionmentioning

confidence: 99%

“…This was an important question given that some CPPs, specifically those which elevate [Ca 2+ ] i , can trigger lysosomal exocytosis from cells such as the HeLa lines that are considered non-secretory [30]. In concordance with our results, the Tat CPP has no influence upon β-hexosaminidase release from HeLa cells even at a concentration of 20 μM [30]. Our data also identify C105Y as a very promising CPP that could be employed to deliver cargoes into MCs without promoting exocytosis [19].…”

Section: Discussionmentioning

confidence: 99%

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Cell penetrating peptide-mediated transport enables the regulated secretion of accumulated cargoes from mast cells

Howl

Jones

2015

Journal of Controlled Release

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The in vivo utility of technologies employing cell penetrating peptides and bioportides may be compromised by the general capacity of polycationic peptides to activate mast cell secretion. Moreover, the same technologies could be exploited in a clinical setting either to directly modulate intrinsic exocytotic mechanisms or to load mast cells with bioactive cargoes. Comparative investigations identified two cell penetrating vectors, Tat and C105Y, which readily translocate into mast cells without inducing receptor-independent exocytosis. Efficient Tat transduction also enabled the intracellular delivery and accumulation of cargoes within discrete intracellular compartments. A tetramethylrhodamine-Tat conjugate is effectively translocated into the secretory lysosomes of RBL-2H3 cells. In contract, the intracellular delivery of avidin, as a non-covalent complex with a biotinylated Tat vector, is also efficient but the protein is predominantly accumulated outside of secretory lysosomes. Significantly, both cargoes can be subsequently released following mast cell stimulation either by mastoparan, a wasp venom secretagogue, or by the physiological mechanism of antigen-induced aggregation of high affinity IgE receptors. These studies indicate that mast cells could be exploited to direct the delivery of bioactive agents to disease sites as an innovative cell-mediated therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cell penetrating peptide-mediated transport enables the regulated secretion of accumulated cargoes from mast cells

Howl

Jones

2015

Journal of Controlled Release

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“…CPPs translocate into cells without cytotoxic effects, are efficiently internalized across cell membranes and aid in carrying cargo into live cells [18]. Although the internalization mechanisms are debatable, the application of CPPs is growing rapidly [19]. Some studies suggest that CPPs directly penetrate (e.g., carpet, inverted micelle, toroidal) through the lipid bilayer of the cell membrane, and others suggest that CPPs employ diverse endocytic pathways (e.g., macropinocytosis, clathrin-dependent, caveolae-mediated and clathrin-/caveolae-independent) (Figure 1) [16,20,21].…”

mentioning

confidence: 99%

Noncovalently Associated cell-penetrating Peptides for Gene Delivery Applications

et al. 2013

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The use of various cell-penetrating peptides (CPPs) to deliver genetic material for gene therapy applications has been a topic of interest for more than 20 years. The delivery of genetic material by using CPPs can be divided into two categories: covalently bound and electrostatically bound. Complexity of the synthesis procedure can be a significant barrier to translation when using a strategy requiring covalent binding of CPPs. In contrast, electrostatically complexing CPPs with genetic material or with a viral vector is relatively simple and has been demonstrated to improve gene delivery in both in vitro and in vivo studies. This review highlights gene therapy applications of complexes formed noncovalently between CPPs and genetic material or viruses.

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Bioportides: Bioactive cell‐penetrating peptides that modulate cellular dynamics

Lukanowska

Howl

Jones

2013

Biotechnology Journal

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The study and exploitation of cell-penetrating peptides (CPPs) now extends into a third exciting decade. Pharmacokinetic modulators, including the more common sequences Tat, penetratin and transportan-10, markedly enhance the intracellular delivery of small drugs, peptides, oligonucleotides and proteins. We introduced the term bioportide to distinguish cell penetrant peptides with intrinsic bioactivities from more typically inert CPP vectors. Our first examples included rhegnylogically organised bioportides, monomeric peptides presenting pharmacophores for both cellular internalization and bioactivity discontinuously distributed within the primary sequence. However, it is conceptually expedient to employ the same terminology to encompass sychnologic bioportides that comprise an inert CPP vector conjugated to an otherwise impermeable bioactive peptide. In such cases the CPP provides an obvious address function whilst the bioactive cargo, often a protein mimetic sequence, is the message. Additional targeting sequences, usually added as chimeric extensions, can also be accommodated within the design of CPPs and bioportides to enable cell- and tissue-selective targeting. Thus, the identification and exploitation of bioportides provides further scope to employ CPPs as research tools, diagnostics and therapeutics spanning a range of pathologies.

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Cell-penetrating Peptides Split into Two Groups Based on Modulation of Intracellular Calcium Concentration

Cited by 40 publications

References 45 publications

Cell penetrating peptide-mediated transport enables the regulated secretion of accumulated cargoes from mast cells

Cell penetrating peptide-mediated transport enables the regulated secretion of accumulated cargoes from mast cells

Noncovalently Associated cell-penetrating Peptides for Gene Delivery Applications

Bioportides: Bioactive cell‐penetrating peptides that modulate cellular dynamics

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