Pepducins and Other Lipidated Peptides as Mechanistic Probes and Therapeutics

Zhang, Ping; Covic, Lidija; Kuliopulos, Athan

doi:10.1007/978-1-4939-2806-4_13

Cited by 32 publications

(31 citation statements)

References 63 publications

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“…However, its unstrearylated version proved not to be capable of autonomously crossing the cell membrane, suggesting that the lipid tail plays a crucial role in the translocation mechanism. This is consistent not only with previous studies on CPPs, where lipidation is often used to increase the efficiency of the penetration (Lehto et al 2017), but on pepducins in general, where the presence of the tail is a conditio sine qua non the peptide can work as a CPP on its own (Zhang et al 2015). Furthermore, from the DLS analysis and ζ-potential measurements, Dyro 1 proved to be capable to form particles in solution.…”

Section: Discussionsupporting

confidence: 90%

“…In particular, by conjugating lipidated CPPs with an amino acid sequence resembling parts of a functional full-length protein, chimeric peptides, generally labeled as 'pepducins', can be produced. Thanks to these functional domains on their backbone, pepducins are capable, once internalized, of specifically interfering with protein-protein interactions by competitively binding to the target protein (Zhang et al 2015). This has been used in the past, for example, to modulate the response of tyrosine-kinase and angiotensin receptors and clinical trials have recently started for an antiplatelet-agent-acting pepducin (Yu et al 2010(Yu et al , 2015Gurbel et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Mimicry of Dopamine 1 Receptor Signaling with Cell-Penetrating Peptides

Lorenzón

Gestin

Langel

2020

Int J Pept Res Ther

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Supplementary figuresSupplementary figure S1 -Cytotoxicity of Dyro 1 on SH-SY5Y cells after 2hrs treatment. SH-SY5Y cells were treated with increasing concentrations of Dyro 1 for 24hrs. The quantity of lactate dehydrogenase (LDH, a cytosolic enzyme) present in the media was measured as an indicator for membrane disruption and cell death. Data were normalized to the controls: untreated cells were used as negative control (physiological release of LDH in the cell medium; 0%), whereas cells treated with Triton X were used as the positive control (being a detergent, Triton X induces membrane disruption and complete LDH release; 100%). Control samples were examined via microscopy before LDH measurements to check for viability. The experiment was performed three times in triplicates. Due to experimental necessities, the examined Dyro 1 concentration range was 10nM -100µM, which was not enough to build a curve. However, comparing the data to the controls, it was still possible to determine the working concentration range (being its maximum, the peptide concentration inducing 20% of membrane rupture at that timepoint). The EC50 was experimentally determined to be at 100µM.Particle size (d.nm) ζ-potential (mV)

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Mimicry of Dopamine 1 Receptor Signaling with Cell-Penetrating Peptides

Lorenzón

Gestin

Langel

2020

Int J Pept Res Ther

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“…They include the protein-derived CPPs and pepducins that are lipidated peptides that remain tethered to the cell membrane but can interact with an intracellular segment of a GPCR resulting in activation or blockade of downstream signaling. Currently there are pepducin agonists and antagonists for many GPCRs including chemokine receptors, the β 2 adrenoceptor, proteinase activated receptors, sphingosine-1-phosphate receptors, and the apelin receptor (for reviews, see Dimond et al, 2011 ; O’Callaghan et al, 2012 ; Zhang et al, 2015 ).…”

Section: Classification Of Selective Agonists and Antagonistsmentioning

confidence: 99%

Endothelin

et al. 2016

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The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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“…The precise mechanism of action of pepducins is not known, but the fact that both lipidated peptidomimetics and pepducins interact with FPR2 indicates a not yet understood role of FPR2 in recognition of lipopeptides and lipidated peptidomimetics. It has been proposed that when it comes to the action of a pepducin, the fatty acid anchors the molecule in the cell membrane, facilitating interaction between the peptide part and the receptor at the signaling interface (40). However, comparison of the structure-activity relationships for analogues of the FPR2-activating peptidomimetic F2M2 with those of the FPR2-inhibiting F2M1 described earlier (22) reveals differences in the optimal length of the N-terminal fatty acid for activation (12 carbons) and inhibition (at least 16 carbons).…”

Section: Variation Of Hydrophobic Amino Acidmentioning

confidence: 99%

The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase

Holdfeldt

Skovbakke

Winther

et al. 2016

Journal of Biological Chemistry

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Neutrophils expressing formyl peptide receptor 2 (FPR2) play key roles in host defense, immune regulation, and resolution of inflammation. Consequently, the search for FPR2-specific modulators has attracted much attention due to its therapeutic potential. Earlier described agonists for this receptor display potent activity for the human receptor (FPR2) but low activity for the mouse receptor orthologue (Fpr2), rendering them inapplicable in murine models of human disease. Here we describe a novel FPR2 agonist, the proteolytically stable ␣-peptide/␤-pep- The molecular basis for directional neutrophil migration toward inflammatory sites is their ability to sense "danger signals" produced by microorganisms (i.e. pathogen-associated molecular patterns) and damaged host cells or tissues (i.e. damage-associated molecular patterns) (1). Human neutrophils express two members of the formyl peptide receptor family (FPR1 3 and FPR2), belonging to the family of G-protein-coupled receptors (GPCRs), which recognize pathogen-associated molecular patterns in the form of peptides with an N-terminal formyl-methionine residue, originating from bacterial (and mitochondrial) protein synthesis (2, 3). In addition, human neutrophils express GPCRs that recognize endogenous chemoattractants and damage-associated molecular patterns, including the split product of complement component C5 (C5a, recognized by C5aR), leukotriene LTB 4 (recognized by BLT1), the chemokine IL-8 (CXCL8, recognized by CXCR1 and CXCR2), platelet-activating factor (PAF, recognized by PAFR), and the nucleotide ATP (recognized by P2Y 2 R) (4, 5). Although the two human neutrophil FPRs, FPR1 and FPR2, display significant sequence similarity, they have distinct, albeit partially overlapping, ligand recognition profiles (2, 6, 7).The mouse genome contains at least eight mouse Fprs, among which Fpr1 and Fpr2 are regarded as the orthologues of the receptors expressed in human neutrophils (8, 9). Studies using mice deficient in Fpr1 or Fpr2 have demonstrated roles of these receptors not only in host defense but also in immune regulation and in the resolution of inflammation (10 -12). The therapeutic potential of targeting these receptors in inflammatory/infectious conditions, such as atherosclerosis, cancer, neurodegenerative diseases, and sepsis (see a recent review (13)), justifies the search for receptor-specific ligands that can function as agonists, antagonists, or allosteric modulators. However, a direct translation of knowledge between humans and

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Pepducins and Other Lipidated Peptides as Mechanistic Probes and Therapeutics

Cited by 32 publications

References 63 publications

Mimicry of Dopamine 1 Receptor Signaling with Cell-Penetrating Peptides

Mimicry of Dopamine 1 Receptor Signaling with Cell-Penetrating Peptides

Endothelin

The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase

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