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| Home > Articles > Published articles > Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems |
| Home > Articles > Published articles > Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems |
(Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Química) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Institut de Química Avançada de Catalunya) (Centro de Investigaciones Biológicas (Madrid)) (Universitat Autònoma de Barcelona. Departament de Química)
| Date: | 2020 |
| Abstract: | Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1S,2R)-3-amino2,2,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. |
| Grants: | Ministerio de Sanidad y Consumo CB/06/01/0074 Ministerio de Economía, Industria y Competitividad CTQ2016-77978-R Ministerio de Economía y Competitividad RD16/0027/0010 Agencia Estatal de Investigación MAT2017-86357-C3-3-R Ministerio de Economía y Competitividad SAF2014-60138-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-503 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1439 |
| Note: | Altres ajuts: CSIC (PIE 201620E038) |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Unnatural γ-amino acids ; Foldamers ; Selective cell-penetrating peptides ; Anti-Leishmania ; Drug delivery vectors |
| Published in: | International journal of molecular sciences, Vol. 21, Num. 20 (October 2020) , art. 7502, ISSN 1422-0067 |
