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Peptidomimetic-based antibody surrogate for HER2
Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to prot...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463277/ https://www.ncbi.nlm.nih.gov/pubmed/34589386 http://dx.doi.org/10.1016/j.apsb.2021.04.016 |
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author | Zheng, Mengmeng Li, Chunpu Zhou, Mi Jia, Ru She, Fengyu Wei, Lulu Cheng, Feng Li, Qi Cai, Jianfeng Wang, Yan |
author_facet | Zheng, Mengmeng Li, Chunpu Zhou, Mi Jia, Ru She, Fengyu Wei, Lulu Cheng, Feng Li, Qi Cai, Jianfeng Wang, Yan |
author_sort | Zheng, Mengmeng |
collection | PubMed |
description | Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on γ-AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic γ-AApeptides, from which we identified a γ-AApeptide, M-3-6, that tightly binds to HER2 selectively. Subsequently, we designed an antibody-like dimer of M-3-6, named M-3-6-D, which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies. Intriguingly, M-3-6-D was completely resistant toward enzymatic degradation. In addition, it could effectively inhibit the phosphorylation of HER2, as well as the downstream signaling pathways of AKT and ERK. Furthermore, M-3-6-D also efficiently inhibited cell proliferation in vitro, and suppressed tumor growth in SKBR3 xenograft model in vivo, implying its therapeutic potential for the treatment of cancers. Its small molecular weight, antibody-like property, resistance to proteolysis, may enable it a new generation of artificial antibody surrogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic γ-AApeptides could be applied to a myriad of disease-related receptor targets in future. |
format | Online Article Text |
id | pubmed-8463277 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84632772021-09-28 Peptidomimetic-based antibody surrogate for HER2 Zheng, Mengmeng Li, Chunpu Zhou, Mi Jia, Ru She, Fengyu Wei, Lulu Cheng, Feng Li, Qi Cai, Jianfeng Wang, Yan Acta Pharm Sin B Original Article Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on γ-AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic γ-AApeptides, from which we identified a γ-AApeptide, M-3-6, that tightly binds to HER2 selectively. Subsequently, we designed an antibody-like dimer of M-3-6, named M-3-6-D, which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies. Intriguingly, M-3-6-D was completely resistant toward enzymatic degradation. In addition, it could effectively inhibit the phosphorylation of HER2, as well as the downstream signaling pathways of AKT and ERK. Furthermore, M-3-6-D also efficiently inhibited cell proliferation in vitro, and suppressed tumor growth in SKBR3 xenograft model in vivo, implying its therapeutic potential for the treatment of cancers. Its small molecular weight, antibody-like property, resistance to proteolysis, may enable it a new generation of artificial antibody surrogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic γ-AApeptides could be applied to a myriad of disease-related receptor targets in future. Elsevier 2021-09 2021-05-01 /pmc/articles/PMC8463277/ /pubmed/34589386 http://dx.doi.org/10.1016/j.apsb.2021.04.016 Text en © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Zheng, Mengmeng Li, Chunpu Zhou, Mi Jia, Ru She, Fengyu Wei, Lulu Cheng, Feng Li, Qi Cai, Jianfeng Wang, Yan Peptidomimetic-based antibody surrogate for HER2 |
title | Peptidomimetic-based antibody surrogate for HER2 |
title_full | Peptidomimetic-based antibody surrogate for HER2 |
title_fullStr | Peptidomimetic-based antibody surrogate for HER2 |
title_full_unstemmed | Peptidomimetic-based antibody surrogate for HER2 |
title_short | Peptidomimetic-based antibody surrogate for HER2 |
title_sort | peptidomimetic-based antibody surrogate for her2 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463277/ https://www.ncbi.nlm.nih.gov/pubmed/34589386 http://dx.doi.org/10.1016/j.apsb.2021.04.016 |
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