scholarly journals Coupling the Antimalarial Cell Penetrating Peptide TP10 to Classical Antimalarial Drugs Primaquine and Chloroquine Produces Strongly Hemolytic Conjugates

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4559 ◽  
Author(s):  
Luísa Aguiar ◽  
Arnau Biosca ◽  
Elena Lantero ◽  
Jiri Gut ◽  
Nuno Vale ◽  
...  
Keyword(s):  
Cell Penetrating Peptides ◽  
Antiplasmodial Activity ◽  
Erythrocyte Membranes ◽  
Cell Penetrating Peptide ◽  
Peptide Conjugates ◽  
Drug Conjugates ◽  
Cell Penetrating ◽  
A Cell ◽  
Peptide Drug Conjugates ◽  
The Cost

Recently, we disclosed primaquine cell penetrating peptide conjugates that were more potent than parent primaquine against liver stage Plasmodium parasites and non-toxic to hepatocytes. The same strategy was now applied to the blood-stage antimalarial chloroquine, using a wide set of peptides, including TP10, a cell penetrating peptide with intrinsic antiplasmodial activity. Chloroquine-TP10 conjugates displaying higher antiplasmodial activity than the parent TP10 peptide were identified, at the cost of an increased hemolytic activity, which was further confirmed for their primaquine analogues. Fluorescence microscopy and flow cytometry suggest that these drug-peptide conjugates strongly bind, and likely destroy, erythrocyte membranes. Taken together, the results herein reported put forward that coupling antimalarial aminoquinolines to cell penetrating peptides delivers hemolytic conjugates. Hence, despite their widely reported advantages as carriers for many different types of cargo, from small drugs to biomacromolecules, cell penetrating peptides seem unsuitable for safe intracellular delivery of antimalarial aminoquinolines due to hemolysis issues. This highlights the relevance of paying attention to hemolytic effects of cell penetrating peptide-drug conjugates.

scholarly journals Insights into the Membranolytic Activity of Antimalarial Drug-Cell Penetrating Peptide Conjugates

Membranes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 4
Author(s):  
Luísa Aguiar ◽  
Marina Pinheiro ◽  
Ana Rute Neves ◽  
Nuno Vale ◽  
Sira Defaus ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Haemolytic Activity ◽  
Cell Penetrating Peptide ◽  
Peptide Conjugates ◽  
Liver Stage ◽  
Cell Penetrating ◽  
A Cell ◽  
The Cost ◽  
Insight Into ◽  
Antimalarial Action

Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well-known antimalarial drugs chloroquine and primaquine has been previously shown to enhance the peptide’s action against, respectively, blood- and liver-stage malaria parasites. Yet, this was achieved at the cost of a significant increase in haemolytic activity, as fluorescence microscopy and flow cytometry studies showed the conjugates to be more haemolytic for non-infected than for Plasmodium-infected red blood cells. To gain further insight into how these conjugates distinctively bind, and likely disrupt, membranes of both Plasmodium-infected and non-infected erythrocytes, we used dynamic light scattering and surface plasmon resonance to study the interactions of two representative conjugates and their parent compounds with lipid model membranes. Results obtained are herein reported and confirm that a strong membrane-disruptive character underlies the haemolytic properties of these conjugates, thus hampering their ability to exert selective antimalarial action.

scholarly journals A comparison of acyl-moieties for noncovalent functionalization of PLGA and PEG-PLGA nanoparticles with a cell-penetrating peptide

RSC Advances ◽  
2021 ◽  
Vol 11 (57) ◽  
pp. 36116-36124
Author(s):  
Omar Paulino da Silva Filho ◽  
Muhanad Ali ◽  
Rike Nabbefeld ◽  
Daniel Primavessy ◽  
Petra H. Bovee-Geurts ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Plga Nanoparticles ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Noncovalent Functionalization ◽  
Cell Penetrating ◽  
A Cell

Noncovalent functionalization with acylated cell-penetrating peptides achieves an efficient cellular uptake of PLGA and PEG-PLGA nanoparticles.

Novel cleavable cell-penetrating peptide-drug conjugates: synthesis and characterization

2014 ◽  
Vol 20 (5) ◽  
pp. 323-333 ◽  
Author(s):  
Marco Lelle ◽  
Stefanie U. Frick ◽  
Kerstin Steinbrink ◽  
Kalina Peneva
Keyword(s):  
Synthesis And Characterization ◽  
Cell Penetrating Peptide ◽  
Peptide Drug ◽  
Drug Conjugates ◽  
Cell Penetrating ◽  
Peptide Drug Conjugates

The interfacial electrostatic potential modulates the insertion of cell-penetrating peptides into lipid bilayers

2018 ◽  
Vol 20 (7) ◽  
pp. 5180-5189 ◽  
Author(s):  
Matías A. Via ◽  
Joaquín Klug ◽  
Natalia Wilke ◽  
Luis S. Mayorga ◽  
M. G. Del Pópolo
Keyword(s):  
Lipid Bilayers ◽  
Charge Compensation ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Compensation Mechanism ◽  
Counter Ions ◽  
Cell Penetrating ◽  
A Cell ◽  
A Charge ◽  
Peptide Insertion

A charge compensation mechanism, arising from the segregation of counter-ions while a cell-penetrating-peptide traverses a membrane, determines the shape and symmetry of the peptide insertion free-energy profile.

scholarly journals Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides

2020 ◽  
Vol 8 (47) ◽  
pp. 10825-10836
Author(s):  
Carmine Pasquale Cerrato ◽  
Tove Kivijärvi ◽  
Roberta Tozzi ◽  
Tõnis Lehto ◽  
Maxime Gestin ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Intracellular Delivery ◽  
Cell Penetrating Peptides ◽  
Peptide Library ◽  
Mitochondrial Proteins ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
A Cell

Development of a cell-penetrating peptide library to deliver biomolecules affecting mitochondria functionalities by targeting genes coding for mitochondrial proteins.

scholarly journals Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

2012 ◽  
Vol 8 ◽  
pp. 1788-1797 ◽  
Author(s):  
Jan Hoyer ◽  
Ulrich Schatzschneider ◽  
Michaela Schulz-Siegmund ◽  
Ines Neundorf
Keyword(s):  
Drug Delivery ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cellular Uptake ◽  
Cell Penetrating Peptides ◽  
Antimicrobial Protein ◽  
Cell Penetrating Peptide ◽  
Specific Cell ◽  
Cell Penetrating ◽  
A Cell

Over the past 20 years, cell-penetrating peptides (CPPs) have gained tremendous interest due to their ability to deliver a variety of therapeutically active molecules that would otherwise be unable to cross the cellular membrane due to their size or hydrophilicity. Recently, we reported on the identification of a novel CPP, sC18, which is derived from the C-terminus of the 18 kDa cationic antimicrobial protein. Furthermore, we demonstrated successful application of sC18 for the delivery of functionalized cyclopentadienyl manganese tricarbonyl (cymantrene) complexes to tumor cell lines, inducing high cellular toxicity. In order to increase the potential of the organometallic complexes to kill tumor cells, we were looking for a way to enhance cellular uptake. Therefore, we designed a branched dimeric variant of sC18, (sC18)2, which was shown to have a dramatically improved capacity to internalize into various cell lines, even primary cells, using flow cytometry and fluorescence microscopy. Cell viability assays indicated increased cytotoxicity of the dimer presumably caused by membrane leakage; however, this effect turned out to be dependent on the specific cell type. Finally, we could show that conjugation of a functionalized cymantrene with (sC18)2leads to significant reduction of its IC50value in tumor cells compared to the respective sC18 conjugate, proving that dimerization is a useful method to increase the drug-delivery potential of a cell-penetrating peptide.

scholarly journals Click to enter: activation of oligo-arginine cell-penetrating peptides by bioorthogonal tetrazine ligations

2019 ◽  
Vol 10 (3) ◽  
pp. 701-705 ◽  
Author(s):  
Saskia A. Bode ◽  
Suzanne B. P. E. Timmermans ◽  
Selma Eising ◽  
Sander P. W. van Gemert ◽  
Kimberly M. Bonger ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
A Cell

The cellular uptake of a cell-penetrating peptide is controlled by reconstitution of two inactive halves using bioorthogonal tetrazine ligations and is applied to a fluorescently labelled protein.

scholarly journals Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

2018 ◽  
Vol 14 ◽  
pp. 1378-1388 ◽  
Author(s):  
Anja Gronewold ◽  
Mareike Horn ◽  
Ines Neundorf
Keyword(s):  
Cellular Uptake ◽  
Cell Penetrating Peptides ◽  
Nuclear Localization Sequence ◽  
Biological Characterization ◽  
Cell Nuclei ◽  
Drug Conjugates ◽  
Cell Penetrating ◽  
Localization Sequence ◽  
Peptide Drug Conjugates

Within this study, we report about the design and biological characterization of novel cell-penetrating peptides (CPPs) with selective suborganelle-targeting properties. The nuclear localization sequence N50, as well as the nucleoli-targeting sequence NrTP, respectively, were fused to a shortened version of the cell-penetrating peptide sC18. We examined cellular uptake, subcellular fate and cytotoxicity of these novel peptides, N50-sC18* and NrTP-sC18*, and found that they are nontoxic up to a concentration of 50 or 100 µM depending on the cell lines used. Moreover, detailed cellular uptake studies revealed that both peptides enter cells via energy-independent uptake, although endocytotic processes cannot completely excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide–drug conjugates.

scholarly journals Coupling the cell-penetrating peptides transportan and transportan 10 to primaquine enhances its activity against liver-stage malaria parasites

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 221-226 ◽  
Author(s):  
Luísa Aguiar ◽  
Marta Machado ◽  
Margarida Sanches-Vaz ◽  
Miguel Prudêncio ◽  
Nuno Vale ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Parent Drug ◽  
Cell Penetrating Peptides ◽  
Cell Penetrating Peptide ◽  
Malaria Parasites ◽  
Peptide Conjugates ◽  
Liver Stage ◽  
Cell Penetrating

Novel primaquine–cell penetrating peptide conjugates were synthesised and testedin vitroagainst liver stagePlasmodium bergheiparasites, showing that generally the conjugates were more active than the parent peptides and, in some cases, than the parent drug.

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