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Open AccessArticle

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

1
LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
2
Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, 08036 Barcelona, Spain
3
Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
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School of Medicine, University of California at San Francisco, 1001 Potrero Avenue, San Francisco, San Francisco, CA 94110, USA
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Departamento de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia da Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
6
IPATIMUP—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
7
i3S, Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
8
Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-008 Lisbon, Portugal
9
Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Dr. Aiguader 88, 08003 Barcelona, Spain
10
Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Steven L. Cobb
Molecules 2019, 24(24), 4559; https://doi.org/10.3390/molecules24244559
Received: 25 October 2019 / Revised: 5 December 2019 / Accepted: 10 December 2019 / Published: 12 December 2019
(This article belongs to the Special Issue Bioactive Peptides—From Therapy to Nutrition)
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. View Full-Text
Keywords: antimalarial; cell penetrating peptide; chloroquine; erythrocyte fluorescence; flow cytometry; hemolysis; microscopy; Plasmodium; primaquine; red blood cell antimalarial; cell penetrating peptide; chloroquine; erythrocyte fluorescence; flow cytometry; hemolysis; microscopy; Plasmodium; primaquine; red blood cell
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MDPI and ACS Style

Aguiar, L.; Biosca, A.; Lantero, E.; Gut, J.; Vale, N.; Rosenthal, P.J.; Nogueira, F.; Andreu, D.; Fernàndez-Busquets, X.; Gomes, P. Coupling the Antimalarial Cell Penetrating Peptide TP10 to Classical Antimalarial Drugs Primaquine and Chloroquine Produces Strongly Hemolytic Conjugates. Molecules 2019, 24, 4559.

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