Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems
Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1<i>S</i>,2<i>R</i>)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a <i>N</i><sup>α</sup>-functionalized <i>cis</i>- or <i>trans</i>-γ...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7502 |
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| author | Ona Illa José-Antonio Olivares Nerea Gaztelumendi Laura Martínez-Castro Jimena Ospina María-Ángeles Abengozar Giuseppe Sciortino Jean-Didier Maréchal Carme Nogués Míriam Royo Luis Rivas Rosa M. Ortuño |
| author_facet | Ona Illa José-Antonio Olivares Nerea Gaztelumendi Laura Martínez-Castro Jimena Ospina María-Ángeles Abengozar Giuseppe Sciortino Jean-Didier Maréchal Carme Nogués Míriam Royo Luis Rivas Rosa M. Ortuño |
| author_sort | Ona Illa |
| collection | DOAJ |
| description | Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1<i>S</i>,2<i>R</i>)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a <i>N</i><sup>α</sup>-functionalized <i>cis</i>- or <i>trans</i>-γ-amino-<span style="font-variant: small-caps;">l</span>-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-<i>Leishmania</i> 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 <i>Leishmania</i> 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. |
| first_indexed | 2024-03-10T15:41:36Z |
| format | Article |
| id | doaj.art-976a732b116b4ee8b16dc87fd4099408 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:41:36Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-976a732b116b4ee8b16dc87fd40994082023-11-20T16:45:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120750210.3390/ijms21207502Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery SystemsOna Illa0José-Antonio Olivares1Nerea Gaztelumendi2Laura Martínez-Castro3Jimena Ospina4María-Ángeles Abengozar5Giuseppe Sciortino6Jean-Didier Maréchal7Carme Nogués8Míriam Royo9Luis Rivas10Rosa M. Ortuño11Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainCentro de Investigaciones Biológicas Margarita Salas, CSIC, c/Ramiro de Maeztu, 9, 28040 Madrid, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainDepartament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainInstitut de Química Avançada de Catalunya (IQAC-CSIC), c/Jordi Girona, 18–26, 08034 Barcelona, SpainCentro de Investigaciones Biológicas Margarita Salas, CSIC, c/Ramiro de Maeztu, 9, 28040 Madrid, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, SpainTwo series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1<i>S</i>,2<i>R</i>)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a <i>N</i><sup>α</sup>-functionalized <i>cis</i>- or <i>trans</i>-γ-amino-<span style="font-variant: small-caps;">l</span>-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-<i>Leishmania</i> 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 <i>Leishmania</i> 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.https://www.mdpi.com/1422-0067/21/20/7502unnatural γ-amino acidsfoldamersselective cell-penetrating peptidesanti-<i>Leishmania</i> drug delivery vectors |
| spellingShingle | Ona Illa José-Antonio Olivares Nerea Gaztelumendi Laura Martínez-Castro Jimena Ospina María-Ángeles Abengozar Giuseppe Sciortino Jean-Didier Maréchal Carme Nogués Míriam Royo Luis Rivas Rosa M. Ortuño Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems International Journal of Molecular Sciences unnatural γ-amino acids foldamers selective cell-penetrating peptides anti-<i>Leishmania</i> drug delivery vectors |
| title | Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems |
| title_full | Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems |
| title_fullStr | Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems |
| title_full_unstemmed | Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems |
| title_short | Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-<i>Leishmania</i> Drug Delivery Systems |
| title_sort | chiral cyclobutane containing cell penetrating peptides as selective vectors for anti i leishmania i drug delivery systems |
| topic | unnatural γ-amino acids foldamers selective cell-penetrating peptides anti-<i>Leishmania</i> drug delivery vectors |
| url | https://www.mdpi.com/1422-0067/21/20/7502 |
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