Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

Abstract Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to c...

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Autores principales:	D. Thean, J. S. Ebo, T. Luxton, Xue’Er Cheryl Lee, T. Y. Yuen, F. J. Ferrer, C. W. Johannes, D. P. Lane, C. J. Brown
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5cc897bcbc9a4ba18063d8ebc7a1fd3e
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spelling	oai:doaj.org-article:5cc897bcbc9a4ba18063d8ebc7a1fd3e2021-12-02T11:40:22ZEnhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery10.1038/s41598-017-01712-52045-2322https://doaj.org/article/5cc897bcbc9a4ba18063d8ebc7a1fd3e2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01712-5https://doaj.org/toc/2045-2322Abstract Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies underscore that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides.D. TheanJ. S. EboT. LuxtonXue’Er Cheryl LeeT. Y. YuenF. J. FerrerC. W. JohannesD. P. LaneC. J. BrownNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q D. Thean J. S. Ebo T. Luxton Xue’Er Cheryl Lee T. Y. Yuen F. J. Ferrer C. W. Johannes D. P. Lane C. J. Brown Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
description	Abstract Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies underscore that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides.
format	article
author	D. Thean J. S. Ebo T. Luxton Xue’Er Cheryl Lee T. Y. Yuen F. J. Ferrer C. W. Johannes D. P. Lane C. J. Brown
author_facet	D. Thean J. S. Ebo T. Luxton Xue’Er Cheryl Lee T. Y. Yuen F. J. Ferrer C. W. Johannes D. P. Lane C. J. Brown
author_sort	D. Thean
title	Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
title_short	Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
title_full	Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
title_fullStr	Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
title_full_unstemmed	Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
title_sort	enhancing specific disruption of intracellular protein complexes by hydrocarbon stapled peptides using lipid based delivery
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/5cc897bcbc9a4ba18063d8ebc7a1fd3e
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Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

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