Hybrid cyclobutane/proline-containing peptidomimetics: The conformational constraint influences their cell-penetration ability

Ona Illa*, Jimena Ospina, José Emilio Sánchez-Aparicio, Ximena Pulido, María Ángeles Abengozar, Nerea Gaztelumendi, Daniel Carbajo, Carme Nogués, Luis Rivas, Jean Didier Maréchal, Miriam Royo*, Rosa M. Ortuño*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)
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A new family of hybrid β,γ-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing trans-β-amino acid plus a Nα-functionalized trans-γ-amino-L-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapep-tide showed a substantial microbicidal activity on Leishmania parasites at 50 µM but with a modest intracellular accumulation. Their previously published γ,γ-homologues, with a cyclobutane γ-amino acid, showed a well-defined secondary structure with an average inter-guanidinium distance of 8–10 Å, a higher leishmanicidal activity as well as a significant intracellular accumulation. The presence of a very rigid cyclobutane β-amino acid in the peptide backbone precludes the acquisition of a defined conformation suitable for their cell uptake ability. Our results unveiled the preor-ganized charge-display as a relevant parameter, additional to the separation among the charged groups as previously described. The data herein reinforce the relevance of these descriptors in the design of CPPs with improved properties.

Original languageEnglish
Article number5092
Number of pages18
JournalInternational journal of molecular sciences
Issue number10
Publication statusPublished - 2 May 2021


  • Cell penetrating peptides
  • Charge-preorganization
  • Conformational bias
  • Peptidomimetics
  • Rigidity


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