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Title

De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators

AuthorsBonache de Marcos, María Ángeles ; Balsera, Beatriz; López-Méndez, Blanca; Millet, Óscar; Brancaccio, Diego; Gómez-Monterrey, Isabel; Carotenuto, Alfonso; Pavone, Luigi M.; 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
KeywordsPeptides
α-helix
NMR
Protein-protein interactions
P53-MDM2
VEGF-FIt-1
ThermoTRPs
TRPA1
Issue Date2014
PublisherAmerican Chemical Society
CitationACS Combinatorial Science 16: 250- 258 (2014)
AbstractProtein-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.
URIhttp://hdl.handle.net/10261/97782
DOI10.1021/co500005x
Identifiersdoi: 10.1021/co500005x
issn: 2156-8952
e-issn: 2156-8944
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(IBMCP) Artículos
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