Cell-Penetrating Mimics of Agonist-Activated G-Protein Coupled Receptors

Östlund, Pernilla; Kilk, Kalle; Lindgren, Maria; Hällbrink, Mattias; Jiang, Yang; Budihna, Marjan; Černe, Katarina; Bavec, Aljoša; Östenson, Claes‐Göran; Zorko, Matjaž; Langel, Ülo

doi:10.1007/s10989-005-9329-9

Cited by 20 publications

(6 citation statements)

References 38 publications

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“…However, up till now, only a limited number of studies have described the biological activity of CPPs although this information is indicative for potential side effects and relevant for future clinical applications [ 7 , 8 ]. The knowledge on the bioactivity of CPPs is particularly interesting for peptides having an endogenous [ 9 – 13 , 15 – 17 , 19 – 23 ] and viral or bacterial origin [ 14 , 24 – 32 ], as these CPPs can also be endogenously produced during metabolization of their parent protein or peptide.…”

Section: Introductionmentioning

confidence: 99%

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

et al. 2015

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Cell-penetrating peptides (CPPs) are a group of peptides, which have the ability to cross cell membrane bilayers. CPPs themselves can exert biological activity and can be formed endogenously. Fragmentary studies demonstrate their ability to enhance transport of different cargoes across the blood-brain barrier (BBB). However, comparative, quantitative data on the BBB permeability of different CPPs are currently lacking. Therefore, the in vivo BBB transport characteristics of five chemically diverse CPPs, i.e. pVEC, SynB3, Tat 47–57, transportan 10 (TP10) and TP10-2, were determined. The results of the multiple time regression (MTR) analysis revealed that CPPs show divergent BBB influx properties: Tat 47–57, SynB3, and especially pVEC showed very high unidirectional influx rates of 4.73 μl/(g × min), 5.63 μl/(g × min) and 6.02 μl/(g × min), respectively, while the transportan analogs showed a negligible to low brain influx. Using capillary depletion, it was found that 80% of the influxed peptides effectively reached the brain parenchyma. Except for pVEC, all peptides showed a significant efflux out of the brain. Co-injection of pVEC with radioiodinated bovine serum albumin (BSA) did not enhance the brain influx of radiodionated BSA, indicating that pVEC does not itself significantly alter the BBB properties. A saturable mechanism could not be demonstrated by co-injecting an excess dose of non-radiolabeled CPP. No significant regional differences in brain influx were observed, with the exception for pVEC, for which the regional variations were only marginal. The observed BBB influx transport properties cannot be correlated with their cell-penetrating ability, and therefore, good CPP properties do not imply efficient brain influx.

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Section: Introductionmentioning

confidence: 99%

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

et al. 2015

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“…Vazquez et al reported that the synthesized third intracellular loop of the AT1 receptor linked to HIV-TAT was able to be transduced into the hypothalamus and brainstem neurons and increased neuronal firing rate, an effect similar to that observed with angiotensin II stimulation of the neuronal AT1R (21). A more recent study demonstrated that a peptide based on the C-terminus of the AT1 receptor with native cell-penetrating sequences elicits G protein-mediated blood vessel contraction (22), although our IC2 peptide seems evoking an inhibitory effect. Therefore, the activating or inhibiting effects of the intracellular motifs in GPCRs are subtle and complicated.…”

Section: Discussionmentioning

confidence: 99%

Limiting angiotensin II signaling with a cell‐penetrating peptide mimicking the second intracellular loop of the angiotensin II type‐I receptor

Taylor

Mierke

et al. 2010

Chem Biol Drug Des

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A cell-penetrating peptide consisting of the second intracellular loop (IC2) of the Angiotensin II (AngII) type I receptor (AT1) linked to the HIV transactivating regulatory protein (TAT) domain was used to identify the role of this motif for intracellular signal transduction. HEK-293 cells stably transfected with AT1R cDNA and primary cultures of human pulmonary artery smooth muscle cells expressing endogenous AT1 receptor were exposed to the cell-penetrating peptide construct and the effect on angiotensin II signaling determined. The AT1 IC2 peptide effectively inhibited AngII stimulated phosphatidylinositol turnover and calcium influx. It also limited the activation of Akt/PKB as determined by an inhibition of phosphorylation of Akt at Ser473 and completely abolished the AngII dependent activation of the transcriptional factor NFκB. In contrast, the AT1 IC2 peptide had no effect on AngII/AT1 receptor activation of ERK. These results illustrate the potential of using cell penetrating peptides to both delineate receptor-mediated signal transduction as well as to selectively regulate G protein coupled receptor signaling.

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“…This iterative process has been employed to positively identify CPPs from proteins that include G protein-coupled receptors (GPCRs; Ref. 68 …”

Section: Sources Of Bioportidesmentioning

confidence: 99%

“…This iterative process has been employed to positively identify CPPs from proteins that include G protein-coupled receptors (GPCRs; Ref. 68), a quantitatively dominant class of drug target, and cytochrome C, an intracellular regulator of apoptosis (Ref. 37).…”

Section: Introductionmentioning

confidence: 99%

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Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein interactions

Howl

Jones

2015

Expert Rev. Mol. Med.

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Cell-penetrating peptides (CPPs) are reliable vehicles for the target-selective intracellular delivery of therapeutic agents. The identification and application of numerous intrinsically bioactive CPPs, now designated as bioportides, is further endorsement of the tremendous clinical potential of CPP technologies. The refinement of proteomimetic bioportides, particularly sequences that mimic cationic α-helical domains involved in protein-protein interactions (PPIs), provides tremendous opportunities to modulate this emergent drug modality in a clinical setting. Thus, a number of CPP-based constructs are currently undergoing clinical trials as human therapeutics, with a particular focus upon anti-cancer agents. A well-characterised array of synthetic modifications, compatible with modern solid-phase synthesis, can be utilised to improve the biophysical and pharmacological properties of bioportides and so achieve cell-and tissue-selective targeting in vivo. Moreover, considering the recent successful development of stapled α-helical peptides as anti-cancer agents, we hypothesise that similar structural modifications are applicable to the design of bioportides that more effectively modulate the many interactomes known to underlie human diseases. Thus, we propose that stapled-helical bioportides could satisfy all of the clinical requirements for metabolically stable, intrinsically cell-permeable agents capable of regulating discrete PPIs by a dominant negative mode of action with minimal toxicity.

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Cell-Penetrating Mimics of Agonist-Activated G-Protein Coupled Receptors

Cited by 20 publications

References 38 publications

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

Limiting angiotensin II signaling with a cell‐penetrating peptide mimicking the second intracellular loop of the angiotensin II type‐I receptor

Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein interactions

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