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Simultaneous Targeting of Two Master Regulators of Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates
[Image: see text] Conjugation of peptides with oligonucleotides offers opportunities for combining the strengths of both biopolymer classes. Herein, we show that the combination of a peptide-based module with an antisense oligonucleotide module provides for enhancements of potency and a widened scop...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583637/ https://www.ncbi.nlm.nih.gov/pubmed/32567853 http://dx.doi.org/10.1021/acs.bioconjchem.0c00284 |
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author | Altrichter, Yannic Seitz, Oliver |
author_facet | Altrichter, Yannic Seitz, Oliver |
author_sort | Altrichter, Yannic |
collection | PubMed |
description | [Image: see text] Conjugation of peptides with oligonucleotides offers opportunities for combining the strengths of both biopolymer classes. Herein, we show that the combination of a peptide-based module with an antisense oligonucleotide module provides for enhancements of potency and a widened scope of cell delivery options. The peptide unit comprises a Smac mimetic compound (SMCs) which antagonizes the action of inhibitor of apoptosis proteins (IAPs) frequently overexpressed in cancer cells. To counteract SMC resistance, the antisense module downregulates the cellular FLICE-like protein (c-FLIP), a master regulator of the extrinsic apoptosis pathway. We compared c-FLIP antisense units based on oligophosphorothioate (PSO) and peptide nucleic acid (PNA) architectures. Owing to the ease of synthesis, PNA conjugates combined with a cell penetrating peptide (CPP) offer a seemingly ideal solution for cell delivery of dual activity agents. However, our investigations revealed that such congeners have to be handled with care to avoid off-target effects. By contrast, PSO conjugates provided a more robust and specific activity for inducing death of SMC-resistant A549 cells due to a simultaneous activation of caspases and c-FLIP knockdown. We show that lipofection is a convenient approach for delivery of peptide–PSO conjugates into cells. The results highlight that the combination of the peptide and the DNA world confers properties inaccessible by the unconjugated components. |
format | Online Article Text |
id | pubmed-7583637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-75836372021-06-22 Simultaneous Targeting of Two Master Regulators of Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates Altrichter, Yannic Seitz, Oliver Bioconjug Chem [Image: see text] Conjugation of peptides with oligonucleotides offers opportunities for combining the strengths of both biopolymer classes. Herein, we show that the combination of a peptide-based module with an antisense oligonucleotide module provides for enhancements of potency and a widened scope of cell delivery options. The peptide unit comprises a Smac mimetic compound (SMCs) which antagonizes the action of inhibitor of apoptosis proteins (IAPs) frequently overexpressed in cancer cells. To counteract SMC resistance, the antisense module downregulates the cellular FLICE-like protein (c-FLIP), a master regulator of the extrinsic apoptosis pathway. We compared c-FLIP antisense units based on oligophosphorothioate (PSO) and peptide nucleic acid (PNA) architectures. Owing to the ease of synthesis, PNA conjugates combined with a cell penetrating peptide (CPP) offer a seemingly ideal solution for cell delivery of dual activity agents. However, our investigations revealed that such congeners have to be handled with care to avoid off-target effects. By contrast, PSO conjugates provided a more robust and specific activity for inducing death of SMC-resistant A549 cells due to a simultaneous activation of caspases and c-FLIP knockdown. We show that lipofection is a convenient approach for delivery of peptide–PSO conjugates into cells. The results highlight that the combination of the peptide and the DNA world confers properties inaccessible by the unconjugated components. American Chemical Society 2020-06-22 2020-08-19 /pmc/articles/PMC7583637/ /pubmed/32567853 http://dx.doi.org/10.1021/acs.bioconjchem.0c00284 Text en This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Altrichter, Yannic Seitz, Oliver Simultaneous Targeting of Two Master Regulators of Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title | Simultaneous Targeting of Two Master Regulators of
Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title_full | Simultaneous Targeting of Two Master Regulators of
Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title_fullStr | Simultaneous Targeting of Two Master Regulators of
Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title_full_unstemmed | Simultaneous Targeting of Two Master Regulators of
Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title_short | Simultaneous Targeting of Two Master Regulators of
Apoptosis with Dual-Action PNA– and DNA–Peptide Conjugates |
title_sort | simultaneous targeting of two master regulators of
apoptosis with dual-action pna– and dna–peptide conjugates |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583637/ https://www.ncbi.nlm.nih.gov/pubmed/32567853 http://dx.doi.org/10.1021/acs.bioconjchem.0c00284 |
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