Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems
| Autor: | Carme Nogués, María-Ángeles Abengozar, Ona Illa, Luis Rivas, Jean-Didier Maréchal, Giuseppe Sciortino, Nerea Gaztelumendi, José Antonio Olivares, Laura Martínez-Castro, Miriam Royo, Rosa M. Ortuño, Jimena Ospina |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Circular dichroism Selective cell-penetrating peptides Peptide Foldamers 01 natural sciences Catalysis lcsh:Chemistry Inorganic Chemistry HeLa 03 medical and health sciences Anti-Leishmania Physical and Theoretical Chemistry Cytotoxicity lcsh:QH301-705.5 Molecular Biology Spectroscopy chemistry.chemical_classification biology anti-Leishmania drug delivery vectors 010405 organic chemistry Organic Chemistry General Medicine Drug delivery vectors biology.organism_classification 0104 chemical sciences Computer Science Applications 030104 developmental biology Membrane lcsh:Biology (General) lcsh:QD1-999 chemistry Unnatural γ-amino acids Drug delivery Biophysics Intracellular Conjugate |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona International Journal of Molecular Sciences, Vol 21, Iss 7502, p 7502 (2020) International Journal of Molecular Sciences Volume 21 Issue 20 |
| Popis: | Two series of new hybrid &gamma /&gamma peptides, &gamma CC and &gamma CT, formed by (1S,2R)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a N&alpha functionalized cis- or trans-&gamma 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 &gamma CT tetradecamers were microbicidal on the protozoan parasite Leishmania beyond 25 &mu M, with significant intracellular accumulation. They were conjugated to fluorescent doxorubicin (Dox) as a standard drug showing toxicity beyond 1 &mu M, 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-&gamma 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. |
| Databáze: | OpenAIRE |
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