Drug Conjugation Induced Modulation of Structural and Membrane Interaction Features of Cationic Cell-Permeable Peptides

• Published in: International journal of molecular sciences Vol. 21; no. 6; p. 2197
• Main Authors: Pári, Edit, Horváti, Kata, Bősze, Szilvia, Biri-Kovács, Beáta, Szeder, Bálint, Zsila, Ferenc, Kiss, Éva
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.03.2020; MDPI
• Subjects: Acquired immune deficiency syndrome; AIDS; Amino Acid Sequence; Antitubercular Agents - administration & dosage; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacokinetics; atomic force microscopy; Cations; Cell Line, Tumor; Cell walls; cell-penetrating peptides; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - metabolism; Circular dichroism; circular dichroism spectroscopy; Conjugates; Conjugation; Dichroism; Drug carriers; Drug Carriers - chemistry; Drug Carriers - metabolism; Drugs; drug–peptide conjugates; HIV; Human immunodeficiency virus; Humans; Hydrophobicity; Internalization; Investigations; Isoniazid; Isoniazid - administration & dosage; Isoniazid - chemistry; Isoniazid - pharmacokinetics; langmuir monolayer; Lipid Bilayers - metabolism; Lipids; Localization; membrane affinity; Membrane Lipids - metabolism; Membranes; Microscopy; Molecular interactions; Mycobacterium tuberculosis - drug effects; mycolic acid; Pathogens; Peptides; Protein structure; Retention; Secondary structure; Spectrum analysis; Squamous cell carcinoma; Surfactants; Tuberculosis; Tuberculosis - drug therapy; mycolic acid; cell-penetrating peptides; circular dichroism spectroscopy; membrane affinity; Langmuir monolayer; atomic force microscopy; drug–peptide conjugates
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21062197

Cell-penetrating peptides might have great potential for enhancing the therapeutic effect of drug molecules against such dangerous pathogens as (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.