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Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides

Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjug...

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Autores principales: Ivánczi, Márton, Balogh, Balázs, Kis, Loretta, Mándity, István
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535489/
https://www.ncbi.nlm.nih.gov/pubmed/37765059
http://dx.doi.org/10.3390/ph16091251
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author Ivánczi, Márton
Balogh, Balázs
Kis, Loretta
Mándity, István
author_facet Ivánczi, Márton
Balogh, Balázs
Kis, Loretta
Mándity, István
author_sort Ivánczi, Márton
collection PubMed
description Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates. We have selected three CPPs with a linear backbone, including penetratin, a naturally occurring oligopeptide; two of its modified sequence analogues (6,14-Phe-penetratin and dodeca-penetratin); and three natural CPPs with a cyclic backbone: Kalata B1, the Sunflower trypsin inhibitor 1 (SFT1), and Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). We have also built conjugates with the small-molecule drug compounds doxorubicin, zidovudine, and rasagiline for each peptide. Molecular dynamics (MD) simulations were carried out with explicit membrane models. The analysis of the trajectories showed that the interaction of penetratin with the membrane led to spectacular rearrangements in the secondary structure of the peptide, while cyclic peptides remained unchanged due to their high conformational stability. Membrane–peptide and membrane–conjugate interactions have been identified and compared. Taking into account well-known examples from the literature, our simulations demonstrated the utility of computational methods for CPP complexes, and they may contribute to a better understanding of the mechanism of penetration, which could serve as the basis for delivering conjugated drug molecules to their intracellular targets.
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spelling pubmed-105354892023-09-29 Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides Ivánczi, Márton Balogh, Balázs Kis, Loretta Mándity, István Pharmaceuticals (Basel) Article Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates. We have selected three CPPs with a linear backbone, including penetratin, a naturally occurring oligopeptide; two of its modified sequence analogues (6,14-Phe-penetratin and dodeca-penetratin); and three natural CPPs with a cyclic backbone: Kalata B1, the Sunflower trypsin inhibitor 1 (SFT1), and Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). We have also built conjugates with the small-molecule drug compounds doxorubicin, zidovudine, and rasagiline for each peptide. Molecular dynamics (MD) simulations were carried out with explicit membrane models. The analysis of the trajectories showed that the interaction of penetratin with the membrane led to spectacular rearrangements in the secondary structure of the peptide, while cyclic peptides remained unchanged due to their high conformational stability. Membrane–peptide and membrane–conjugate interactions have been identified and compared. Taking into account well-known examples from the literature, our simulations demonstrated the utility of computational methods for CPP complexes, and they may contribute to a better understanding of the mechanism of penetration, which could serve as the basis for delivering conjugated drug molecules to their intracellular targets. MDPI 2023-09-05 /pmc/articles/PMC10535489/ /pubmed/37765059 http://dx.doi.org/10.3390/ph16091251 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ivánczi, Márton
Balogh, Balázs
Kis, Loretta
Mándity, István
Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title_full Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title_fullStr Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title_full_unstemmed Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title_short Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides
title_sort molecular dynamics simulations of drug-conjugated cell-penetrating peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535489/
https://www.ncbi.nlm.nih.gov/pubmed/37765059
http://dx.doi.org/10.3390/ph16091251
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