De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators
Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical intervention because of their essential role in numerous physiological and pathological processes, but screening efforts using small-molecules have led to very low hit rates. Linear peptides could represent a qu...
| Autores: | , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:dnet:digitalcsic_::138aa560b019a0bd5aebb6ff5acd52de |
| Acceso en línea: | http://hdl.handle.net/10261/97782 |
| Access Level: | acceso abierto |
| Palabra clave: | Peptides α-helix NMR Protein-protein interactions P53-MDM2 VEGF-FIt-1 ThermoTRPs TRPA1 |
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De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulatorsBonache de Marcos, María ÁngelesBalsera, BeatrizLópez-Méndez, BlancaMillet, OscarBrancaccio, DiegoGómez-Monterrey, IsabelCarotenuto, AlfonsoPavone, Luigi MicheleReille-Seroussi, MarieGagey-Eilstein, NathalieVidal, MichelTorre-Martínez, Roberto de laFernández-Carvajal, AsiaFerrer-Montiel, AntonioGarcía-López, M. TeresaMartín-Martínez, MercedesPérez de Vega, M. JesúsGonzález-Muñiz, RosarioPeptidesα-helixNMRProtein-protein interactionsP53-MDM2VEGF-FIt-1ThermoTRPsTRPA1Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical intervention because of their essential role in numerous physiological and pathological processes, but screening efforts using small-molecules have led to very low hit rates. Linear peptides could represent a quick and effective approach to discover initial PPI hits, particularly if they have inherent ability to adopt specific peptide secondary structures. Here, we address this hypothesis through a linear helical peptide library, composed of four sublibraries, which was designed by theoretical predictions of helicity (Agadir software). The 13-mer peptides of this collection fixes either a combination of three aromatic or two aromatic and one aliphatic residues on one face of the helix (Ac-SSEEX5ARNX9AAX12N-NH 2), since these are structural features quite common at PPIs interfaces. The 81 designed peptides were conveniently synthesized by parallel solid-phase methodologies, and the tendency of some representative library components to adopt the intended secondary structure was corroborated through CD and NMR experiments. As proof of concept in the search for PPI modulators, the usefulness of this library was verified on the widely studied p53-MDM2 interaction and on the communication between VEGF and its receptor Flt-1, two PPIs for which a hydrophobic α-helix is essential for the interaction. We have demonstrated here that, in both cases, selected peptides from the library, containing the right hydrophobic sequence of the hot-spot in one of the protein partners, are able to interact with the complementary protein. Moreover, we have discover some new, quite potent inhibitors of the VEGF-Flt-1 interaction, just by replacing one of the aromatic residues of the initial F5Y 9Y12 peptide by W, in agreement with previous results on related antiangiogenic peptides. Finally, the HTS evaluation of the full collection on thermoTRPs has led to a few antagonists of TRPV1 and TRPA1 channels, which open new avenues on the way to innovative modulators of these channels.Peer ReviewedAmerican Chemical Society2014201420142014info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/97782reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::138aa560b019a0bd5aebb6ff5acd52de2026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| title |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| spellingShingle |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators Bonache de Marcos, María Ángeles Peptides α-helix NMR Protein-protein interactions P53-MDM2 VEGF-FIt-1 ThermoTRPs TRPA1 |
| title_short |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| title_full |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| title_fullStr |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| title_full_unstemmed |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| title_sort |
De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators |
| dc.creator.none.fl_str_mv |
Bonache de Marcos, María Ángeles Balsera, Beatriz López-Méndez, Blanca Millet, Oscar Brancaccio, Diego Gómez-Monterrey, Isabel Carotenuto, Alfonso Pavone, Luigi Michele Reille-Seroussi, Marie Gagey-Eilstein, Nathalie Vidal, Michel Torre-Martínez, Roberto de la Fernández-Carvajal, Asia Ferrer-Montiel, Antonio García-López, M. Teresa Martín-Martínez, Mercedes Pérez de Vega, M. Jesús González-Muñiz, Rosario |
| author |
Bonache de Marcos, María Ángeles |
| author_facet |
Bonache de Marcos, María Ángeles Balsera, Beatriz López-Méndez, Blanca Millet, Oscar Brancaccio, Diego Gómez-Monterrey, Isabel Carotenuto, Alfonso Pavone, Luigi Michele Reille-Seroussi, Marie Gagey-Eilstein, Nathalie Vidal, Michel Torre-Martínez, Roberto de la Fernández-Carvajal, Asia Ferrer-Montiel, Antonio García-López, M. Teresa Martín-Martínez, Mercedes Pérez de Vega, M. Jesús González-Muñiz, Rosario |
| author_role |
author |
| author2 |
Balsera, Beatriz López-Méndez, Blanca Millet, Oscar Brancaccio, Diego Gómez-Monterrey, Isabel Carotenuto, Alfonso Pavone, Luigi Michele Reille-Seroussi, Marie Gagey-Eilstein, Nathalie Vidal, Michel Torre-Martínez, Roberto de la Fernández-Carvajal, Asia Ferrer-Montiel, Antonio García-López, M. Teresa Martín-Martínez, Mercedes Pérez de Vega, M. Jesús González-Muñiz, Rosario |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Peptides α-helix NMR Protein-protein interactions P53-MDM2 VEGF-FIt-1 ThermoTRPs TRPA1 |
| topic |
Peptides α-helix NMR Protein-protein interactions P53-MDM2 VEGF-FIt-1 ThermoTRPs TRPA1 |
| description |
Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical intervention because of their essential role in numerous physiological and pathological processes, but screening efforts using small-molecules have led to very low hit rates. Linear peptides could represent a quick and effective approach to discover initial PPI hits, particularly if they have inherent ability to adopt specific peptide secondary structures. Here, we address this hypothesis through a linear helical peptide library, composed of four sublibraries, which was designed by theoretical predictions of helicity (Agadir software). The 13-mer peptides of this collection fixes either a combination of three aromatic or two aromatic and one aliphatic residues on one face of the helix (Ac-SSEEX5ARNX9AAX12N-NH 2), since these are structural features quite common at PPIs interfaces. The 81 designed peptides were conveniently synthesized by parallel solid-phase methodologies, and the tendency of some representative library components to adopt the intended secondary structure was corroborated through CD and NMR experiments. As proof of concept in the search for PPI modulators, the usefulness of this library was verified on the widely studied p53-MDM2 interaction and on the communication between VEGF and its receptor Flt-1, two PPIs for which a hydrophobic α-helix is essential for the interaction. We have demonstrated here that, in both cases, selected peptides from the library, containing the right hydrophobic sequence of the hot-spot in one of the protein partners, are able to interact with the complementary protein. Moreover, we have discover some new, quite potent inhibitors of the VEGF-Flt-1 interaction, just by replacing one of the aromatic residues of the initial F5Y 9Y12 peptide by W, in agreement with previous results on related antiangiogenic peptides. Finally, the HTS evaluation of the full collection on thermoTRPs has led to a few antagonists of TRPV1 and TRPA1 channels, which open new avenues on the way to innovative modulators of these channels. |
| publishDate |
2014 |
| dc.date.none.fl_str_mv |
2014 2014 2014 2014 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/97782 |
| url |
http://hdl.handle.net/10261/97782 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
American Chemical Society |
| publisher.none.fl_str_mv |
American Chemical Society |
| dc.source.none.fl_str_mv |
reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
| reponame_str |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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15,811543 |