Hybrid Cyclobutane/Proline-Containing Peptidomimetics: The Conformational Constraint Influences Their Cell-Penetration Ability
| Autor: | Jimena Ospina, Carme Nogués, Daniel Carbajo, Jean-Didier Maréchal, José-Emilio Sánchez-Aparicio, Ona Illa, María Ángeles Abengózar, Nerea Gaztelumendi, Miriam Royo, Ximena Pulido, Rosa M. Ortuño, Luis Rivas |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Peptidomimetic Protein Conformation Cell Cell-Penetrating Peptides Conformational bias 01 natural sciences Cyclobutane HeLa chemistry.chemical_compound Charge-preorganization Biology (General) Protein secondary structure Spectroscopy Leishmania Cell penetrating peptides biology Chemistry General Medicine Computer Science Applications medicine.anatomical_structure rigidity charge-preorganization Rigidity Dimerization Intracellular Proline QH301-705.5 Cell Survival cell penetrating peptides Catalysis Article Inorganic Chemistry 03 medical and health sciences conformational bias medicine Humans Physical and Theoretical Chemistry QD1-999 Molecular Biology 010405 organic chemistry Organic Chemistry biology.organism_classification 0104 chemical sciences 030104 developmental biology Cell culture peptidomimetics Biophysics Peptidomimetics Cyclobutanes HeLa Cells |
| Zdroj: | International Journal of Molecular Sciences Digital.CSIC. Repositorio Institucional del CSIC instname International Journal of Molecular Sciences, Vol 22, Iss 5092, p 5092 (2021) Volume 22 Issue 10 |
| ISSN: | 1422-0067 |
| Popis: | 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 dodecapeptide 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 preorganized 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. The authors would like to thank the staff at the Servei de Microscòpia de la Universitat Autònoma de Barcelona and the Peptide Synthesis Unit of the NANBIOSIS ICTS (U3, CIBER BBN-IQAC-CSIC) for technical assistance. |
| Databáze: | OpenAIRE |
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