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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...

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Autores principales: Altrichter, Yannic, Seitz, Oliver
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
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.
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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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AT seitzoliver simultaneoustargetingoftwomasterregulatorsofapoptosiswithdualactionpnaanddnapeptideconjugates