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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/20/7502 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |