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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8396023 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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