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Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation

Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this stu...

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Autores principales: Yokoo, Hidetomo, Ohoka, Nobumichi, Takyo, Mami, Ito, Takahito, Tsuchiya, Keisuke, Kurohara, Takashi, Fukuhara, Kiyoshi, Inoue, Takao, Naito, Mikihiko, Demizu, Yosuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396023/
https://www.ncbi.nlm.nih.gov/pubmed/34445478
http://dx.doi.org/10.3390/ijms22168772
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author Yokoo, Hidetomo
Ohoka, Nobumichi
Takyo, Mami
Ito, Takahito
Tsuchiya, Keisuke
Kurohara, Takashi
Fukuhara, Kiyoshi
Inoue, Takao
Naito, Mikihiko
Demizu, Yosuke
author_facet Yokoo, Hidetomo
Ohoka, Nobumichi
Takyo, Mami
Ito, Takahito
Tsuchiya, Keisuke
Kurohara, Takashi
Fukuhara, Kiyoshi
Inoue, Takao
Naito, Mikihiko
Demizu, Yosuke
author_sort Yokoo, Hidetomo
collection PubMed
description Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders.
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spelling pubmed-83960232021-08-28 Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation Yokoo, Hidetomo Ohoka, Nobumichi Takyo, Mami Ito, Takahito Tsuchiya, Keisuke Kurohara, Takashi Fukuhara, Kiyoshi Inoue, Takao Naito, Mikihiko Demizu, Yosuke Int J Mol Sci Article Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders. MDPI 2021-08-16 /pmc/articles/PMC8396023/ /pubmed/34445478 http://dx.doi.org/10.3390/ijms22168772 Text en © 2021 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
Yokoo, Hidetomo
Ohoka, Nobumichi
Takyo, Mami
Ito, Takahito
Tsuchiya, Keisuke
Kurohara, Takashi
Fukuhara, Kiyoshi
Inoue, Takao
Naito, Mikihiko
Demizu, Yosuke
Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title_full Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title_fullStr Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title_full_unstemmed Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title_short Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation
title_sort peptide stapling improves the sustainability of a peptide-based chimeric molecule that induces targeted protein degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396023/
https://www.ncbi.nlm.nih.gov/pubmed/34445478
http://dx.doi.org/10.3390/ijms22168772
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