Drug conjugation induced modulation of structural and membrane interaction features of cationic cell-permeable peptides

Edit Pári (Lead / Corresponding author), Kata Horváti, Szilvia Bősze, Beáta Biri-Kovács, Bálint Szeder, Ferenc Zsila, Éva Kiss (Lead / Corresponding author)

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Abstract

Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as Mycobacterium tuberculosis (Mtb), which causes a major health problem worldwide. A set of cationic cell-penetration peptides with various hydrophobicity were selected and synthesized as drug carrier of isoniazid (INH), a first-line antibacterial agent against tuberculosis. Molecular interactions between the peptides and their INH-conjugates with cell-membrane-forming lipid layers composed of DPPC and mycolic acid (a characteristic component of Mtb cell wall) were evaluated, using the Langmuir balance technique. Secondary structure of the INH conjugates was analyzed and compared to that of the native peptides by circular dichroism spectroscopic experiments performed in aqueous and membrane mimetic environment. A correlation was found between the conjugation induced conformational and membrane affinity changes of the INH–peptide conjugates. The degree and mode of interaction were also characterized by AFM imaging of penetrated lipid layers. In vitro biological evaluation was performed with Penetratin and Transportan conjugates. Results showed similar internalization rate into EBC-1 human squamous cell carcinoma, but markedly different subcellular localization and activity on intracellular Mtb.

Original languageEnglish
Article number2197
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume21
Issue number6
DOIs
Publication statusPublished - 22 Mar 2020

Keywords

  • Atomic force microscopy
  • Cell-penetrating peptides
  • Circular dichroism spectroscopy
  • Drug
  • Langmuir monolayer
  • Membrane affinity
  • Mycolic acid
  • Peptide conjugates

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