Chiral cyclobutane-containing cell-penetrating peptides as selective vectors for anti-leishmania drug delivery systems

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageAmerican English
Article number7502
Pages (from-to)1-24
Number of pages24
JournalInternational Journal of Molecular Sciences
Volume21
Issue number20
DOIs
Publication statusPublished - 12 Oct 2020

Keywords

  • Anti-Leishmania drug delivery vectors
  • Foldamers
  • Selective cell-penetrating peptides
  • Unnatural γ-amino acids
  • TAT PROTEIN
  • NONCOVALENT COMPLEXES
  • TRANSLOCATION
  • MEMBRANE
  • STABILITY
  • DOXORUBICIN
  • -amino acids
  • MECHANISMS
  • foldamers
  • DISPLAY
  • anti-Leishmania drug delivery vectors
  • RESISTANCE
  • RICH
  • selective cell-penetrating peptides
  • unnatural &#947

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