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Set-up and screening of a fragment library targeting the 14-3-3 protein interface

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Abstract

Protein–protein interactions (PPIs) are at the core of regulation mechanisms in biological systems and consequently became an attractive target for therapeutic intervention. PPIs involving the adapter protein 14-3-3 are representative examples given the broad range of partner proteins forming a complex with one of its seven human isoforms. Given the challenges represented by the nature of these interactions, fragment-based approaches offer a valid alternative for the development of PPI modulators. After having assembled a fragment set tailored on PPIs' modulation, we started a screening campaign on the sigma isoform of 14-3-3 adapter proteins. Through the use of both mono- and bi-dimensional nuclear magnetic resonance spectroscopy measurements, coupled with differential scanning fluorimetry, three fragment hits were identified. These molecules bind the protein at two different regions distant from the usual binding groove highlighting new possibilities for selective modulation of 14-3-3 complexes.

Graphical abstract: Set-up and screening of a fragment library targeting the 14-3-3 protein interface

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Publication details

The article was received on 11 Apr 2019, accepted on 20 Jul 2019 and first published on 22 Jul 2019


Article type: Research Article
DOI: 10.1039/C9MD00215D
Med. Chem. Commun., 2019, Advance Article

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    Set-up and screening of a fragment library targeting the 14-3-3 protein interface

    D. Valenti, J. F. Neves, F. Cantrelle, S. Hristeva, D. Lentini Santo, T. Obšil, X. Hanoulle, L. M. Levy, D. Tzalis, I. Landrieu and C. Ottmann, Med. Chem. Commun., 2019, Advance Article , DOI: 10.1039/C9MD00215D

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