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Article

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems

1
Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
2
Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
3
Centro de Investigaciones Biológicas Margarita Salas, CSIC, c/Ramiro de Maeztu, 9, 28040 Madrid, Spain
4
Institut de Química Avançada de Catalunya (IQAC-CSIC), c/Jordi Girona, 18–26, 08034 Barcelona, Spain
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Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), c/Jordi Girona, 18–26, 08034 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7502; https://doi.org/10.3390/ijms21207502
Received: 21 September 2020 / Revised: 6 October 2020 / Accepted: 8 October 2020 / Published: 12 October 2020
(This article belongs to the Collection Feature Papers in Molecular Pharmacology)
Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1S,2R)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a Nα-functionalized cis- or trans-γ-amino-l-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-Leishmania drug delivery systems (DDS). They lacked cytotoxicity on the tumoral human cell line HeLa with a moderate cell-uptake on these cells. In contrast, both γ-CC and γ-CT tetradecamers were microbicidal on the protozoan parasite Leishmania beyond 25 μM, with significant intracellular accumulation. They were conjugated to fluorescent doxorubicin (Dox) as a standard drug showing toxicity beyond 1 μM, while free Dox was not toxic. Intracellular accumulation was 2.5 higher than with Dox-TAT conjugate (TAT = transactivator of transcription, taken as a standard CPP). The conformational structure of the conjugates was approached both by circular dichroism spectroscopy and molecular dynamics simulations. Altogether, computational calculations predict that the drug-γ-peptide conjugates adopt conformations that bury the Dox moiety into a cavity of the folded peptide, while the positively charged guanidinium groups face the solvent. The favorable charge/hydrophobicity balance in these CPP improves the solubility of Dox in aqueous media, as well as translocation across cell membranes, making them promising candidates for DDS. View Full-Text
Keywords: unnatural γ-amino acids; foldamers; selective cell-penetrating peptides; anti-Leishmania drug delivery vectors unnatural γ-amino acids; foldamers; selective cell-penetrating peptides; anti-Leishmania drug delivery vectors
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MDPI and ACS Style

Illa, O.; Olivares, J.-A.; Gaztelumendi, N.; Martínez-Castro, L.; Ospina, J.; Abengozar, M.-Á.; Sciortino, G.; Maréchal, J.-D.; Nogués, C.; Royo, M.; Rivas, L.; Ortuño, R.M. Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems. Int. J. Mol. Sci. 2020, 21, 7502. https://doi.org/10.3390/ijms21207502

AMA Style

Illa O, Olivares J-A, Gaztelumendi N, Martínez-Castro L, Ospina J, Abengozar M-Á, Sciortino G, Maréchal J-D, Nogués C, Royo M, Rivas L, Ortuño RM. Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems. International Journal of Molecular Sciences. 2020; 21(20):7502. https://doi.org/10.3390/ijms21207502

Chicago/Turabian Style

Illa, Ona, José-Antonio Olivares, Nerea Gaztelumendi, Laura Martínez-Castro, Jimena Ospina, María-Ángeles Abengozar, Giuseppe Sciortino, Jean-Didier Maréchal, Carme Nogués, Míriam Royo, Luis Rivas, and Rosa M. Ortuño 2020. "Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems" International Journal of Molecular Sciences 21, no. 20: 7502. https://doi.org/10.3390/ijms21207502

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