Partenaires

CNRS
Logo tutelle Logo tutelle


Rechercher

Sur ce site

Sur le Web du CNRS


Accueil du site > Teams > Organic & Medicinal chemistry > CESMA - Design and Synthesis of Analgesic Molecules > Project PDZ

Project PDZ

by Sylvie Ducki - 23 March 2012

All the versions of this article: English , français

Description of project

Studies have shown that the interruption of the interaction between the PDZ protein PSD-95, and the serotonin receptor 5-HT2A by a peptide containing the 9 C-terminal residues of the receptor 5-HT2A (thus preventing the interaction between PSD-95 and 5-HT2A) is accompanied by an analgesic effect in the mice suffering from neuropathic pain [Pichon 2010]. Consequently, it becomes interesting to design and synthesize small inhibiting molecules of PDZ domains.

The problem lies in the selectivity of inhibition. Indeed more than 250 PDZ domains are encoded by the human genome [Ducki 2009]. We thus chose a general approach which aims: 1) to explore the similarities and differences between PDZ domains, 2) to design and synthesize small specific inhibiting molecules.

Our approach thus consists in evaluating bi-ligands interaction with PDZ domains, these bi-ligands constituted by a part interacting with the S0 site (Our choice was made on an indole described in the literature [Fujii 2003, Vogrig 2011] for its interaction with the S0 site) and the other part exploring the site S1 (linker Cn + acid amino). A first series of 16 molecules was prepared and evaluated (linker: C2, C4, C6 + amino acid: Ile, Lis, Trp, Tyr) [Boucherle 2011].

Publications

Boucherle B, Vogrig A, Deokar H, Bouzidi N, Ripoche I, Thomas I, Marin P, Ducki S. (2011) Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains. Bioorg Med Chem 19:4346.

Ducki S, Bennett E (2009) Protein-protein Interactions: Recent Progress in the Development of Selective PDZ Inhibitors. Current Chem Biol. 3:146.

Vogrig A, Boucherle B, Deokar H, Thomas I, Ripoche I, Lian LY, Ducki S. (2011) NMR evaluation of interactions between substituted-indole and PDZ1 domain of PSD-95. Bioorg Med Chem Lett 21:3349.

Grants

ANR-PCV « PDZ-CANPAIN » (2009-2012) Thématique Emergente du Conseil Régional d’Auvergne / FEDER (2009-2012) Postdoc PRES Clermont-Université (2010-2011)

Academic and industrial collaborations

Prof Lu-Yun Lian, Center for Structural Biology, University of Liverpool UK

Prof Christine Courteix, Equipe « Pharmacologie fondamentale et clinique de la Douleur » de l’Institut NeurolDol (UMR1107) à L’Université d’Auvergne, Clermont-Ferrand.

Prof Philippe Marin, Equipe « Sérotonine et Physiologie » de l’Institut Génomique Fonctionnelle (UMR5203), Montpellier.