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Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates
Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological a...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570898/ https://www.ncbi.nlm.nih.gov/pubmed/36235193 http://dx.doi.org/10.3390/molecules27196656 |
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author | Grabeck, Joshua Lützenburg, Tamara Frommelt, Pia Neundorf, Ines |
author_facet | Grabeck, Joshua Lützenburg, Tamara Frommelt, Pia Neundorf, Ines |
author_sort | Grabeck, Joshua |
collection | PubMed |
description | Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18(ΔE), which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol–Michael addition to form novel PDCs. Our results indicate that sC18(ΔE) could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development. |
format | Online Article Text |
id | pubmed-9570898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95708982022-10-17 Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates Grabeck, Joshua Lützenburg, Tamara Frommelt, Pia Neundorf, Ines Molecules Article Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18(ΔE), which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol–Michael addition to form novel PDCs. Our results indicate that sC18(ΔE) could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development. MDPI 2022-10-07 /pmc/articles/PMC9570898/ /pubmed/36235193 http://dx.doi.org/10.3390/molecules27196656 Text en © 2022 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 Grabeck, Joshua Lützenburg, Tamara Frommelt, Pia Neundorf, Ines Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title | Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title_full | Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title_fullStr | Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title_full_unstemmed | Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title_short | Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates |
title_sort | comparing variants of the cell-penetrating peptide sc18 to design peptide-drug conjugates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570898/ https://www.ncbi.nlm.nih.gov/pubmed/36235193 http://dx.doi.org/10.3390/molecules27196656 |
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