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

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.

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

Molecules ◽

10.3390/molecules24244559 ◽

2019 ◽

Vol 24 (24) ◽

pp. 4559 ◽

Cited By ~ 4

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.

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

MedChemComm ◽

10.1039/c8md00447a ◽

2019 ◽

Vol 10 (2) ◽

pp. 221-226 ◽

Cited By ~ 6

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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