Synthesis and evaluation of original analgesics : PDZ domain protein inhibitors
type: Dataset
description: Protein-protein interactions play a central role in the regulation of biological processes and represent a promissing class of therapeutic targets. It has been recently reported that disrupting the interaction between the PDZ protein PSD-95 and the serotonin receptor 5-HT2A induced an antihyperalgesic effect in diabetic rats. In this context, the development of original ligands capable to inhibit specifically this interaction could lead to a new class of analgesic compounds.We carried out the synthesis of three generations of ligands possessing an indole moiety in order to interact with the highly conserved carboxylate-binding loop (GLGF loop) of PSD-95. Two generations of compounds were developed to find out the position and the nature of the substituents furnishing the best interactions. One generation consists of a family of 15 biligands possessing a substituted indole moiety, coupled with a linker (having from 2 to 6 carbon atoms) via an amid function, ended with various amino acids to interact with the S1 site of the protein, in order to obtain specific ligands.By various biological evaluations, NMR HSQC 1H/15N, chromatography affinity assays and in vivo experiments, we identified two promising inhibitors of the interaction PSD-95/5-HT2A with strong interactions with S0 site of PSD-95. For these compounds, we determined the structure of the complex protein/ligand by NMR NOESY experiments. The orientation of one of these molecules in the S0 site allows us to envisage a new generation of ligands capable to interact with the S1 site of the protein.
identifier: NNT: 2012CLF22271
issued: 2026-05-12T05:21:41.076093
language: fr
modified: 2026-05-12T05:21:41.076098
contact point: Organization
  fn: CCSD
keyword: indoles
keyword: infoeu-reposemanticsdoctoralthesis
keyword: inhibiteurs
keyword: inhibitor
keyword: interactions-proteine-proteine
keyword: ligand-pdz
keyword: pdz-ligand
keyword: protein-protein-interactions
keyword: sdvsalife-sciences-q-bioagricultural-sciences
keyword: theses
landing page: https://theses.hal.science/tel-00803458

Synthesis and evaluation of original analgesics : PDZ domain protein inhibitors
type: Distribution
format: HTML
issued: 2026-05-12T05:21:41.082485
modified: 2026-05-12T05:21:41.051969
access URL: https://theses.hal.science/tel-00803458

test_moissonnage_selune
type: Agent