Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides

In cancer, proliferation of malignant cells is driven by overactivation of growth-signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a res...

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Autores: Guardiola Bagán, Salvador, Seco Moral, Jesús, Varese, Monica, Díaz Lobo, Mireia, García Arroyo, Jesús, Teixidó Turà, Meritxell, Nevola, Laura, Giralt Lledó, Ernest
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/121314
Acceso en línea:https://hdl.handle.net/2445/121314
Access Level:acceso abierto
Palabra clave:Càncer
Pèptids
Proteïnes
Cancer
Peptides
Proteins
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spelling Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptidesGuardiola Bagán, SalvadorSeco Moral, JesúsVarese, MonicaDíaz Lobo, MireiaGarcía Arroyo, JesúsTeixidó Turà, MeritxellNevola, LauraGiralt Lledó, ErnestCàncerPèptidsProteïnesCancerPeptidesProteinsIn cancer, proliferation of malignant cells is driven by overactivation of growth-signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a result of its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging protein-protein interactions (PPIs). Herein, we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (i.e., EGF). This design process was guided by the integrated use of in silico methods and biophysical techniques, such as NMR spectroscopy and surface acoustic wave. The best analogues were able to reduce selectively the viability of EGFR+ human cancer cells. In addition to their efficacy, these bicyclic peptides are endowed with exceptional stability and metabolic resistance-two features that make them suitable candidates for in vivo applications.Wiley-VCH2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/121314Articles publicats en revistes (Química Inorgànica i Orgànica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1002/cbic.201700519ChemBioChem, 2018, vol. 4, num. 19, p. 76-84https://doi.org/10.1002/cbic.201700519(c) Wiley-VCH, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1213142026-05-27T06:46:51Z
dc.title.none.fl_str_mv Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
title Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
spellingShingle Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
Guardiola Bagán, Salvador
Càncer
Pèptids
Proteïnes
Cancer
Peptides
Proteins
title_short Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
title_full Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
title_fullStr Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
title_full_unstemmed Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
title_sort Toward a novel drug to target the EGF-EGFR interaction: design of metabolically stable bicyclic peptides
dc.creator.none.fl_str_mv Guardiola Bagán, Salvador
Seco Moral, Jesús
Varese, Monica
Díaz Lobo, Mireia
García Arroyo, Jesús
Teixidó Turà, Meritxell
Nevola, Laura
Giralt Lledó, Ernest
author Guardiola Bagán, Salvador
author_facet Guardiola Bagán, Salvador
Seco Moral, Jesús
Varese, Monica
Díaz Lobo, Mireia
García Arroyo, Jesús
Teixidó Turà, Meritxell
Nevola, Laura
Giralt Lledó, Ernest
author_role author
author2 Seco Moral, Jesús
Varese, Monica
Díaz Lobo, Mireia
García Arroyo, Jesús
Teixidó Turà, Meritxell
Nevola, Laura
Giralt Lledó, Ernest
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Pèptids
Proteïnes
Cancer
Peptides
Proteins
topic Càncer
Pèptids
Proteïnes
Cancer
Peptides
Proteins
description In cancer, proliferation of malignant cells is driven by overactivation of growth-signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a result of its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging protein-protein interactions (PPIs). Herein, we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (i.e., EGF). This design process was guided by the integrated use of in silico methods and biophysical techniques, such as NMR spectroscopy and surface acoustic wave. The best analogues were able to reduce selectively the viability of EGFR+ human cancer cells. In addition to their efficacy, these bicyclic peptides are endowed with exceptional stability and metabolic resistance-two features that make them suitable candidates for in vivo applications.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/121314
url https://hdl.handle.net/2445/121314
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1002/cbic.201700519
ChemBioChem, 2018, vol. 4, num. 19, p. 76-84
https://doi.org/10.1002/cbic.201700519
dc.rights.none.fl_str_mv (c) Wiley-VCH, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Wiley-VCH, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley-VCH
publisher.none.fl_str_mv Wiley-VCH
dc.source.none.fl_str_mv Articles publicats en revistes (Química Inorgànica i Orgànica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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