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Accueil > Equipes de recherche > Pharmacochimie des récepteurs et des transporteurs des α-aminoacides > Thèmes de recherche

Vesicular transporters

publié le , mis à jour le

The second major topic of the group is focused on transporters.
Presynaptic neurotransmitter vesicles play a key role in the neurotransmitter cycle by stocking and releasing it upon action potential. Vesicular neurotransmitter transporters (VNTs) allow the loading of these vesicles and are thus major actors of the neurotransmission. Initially the project aimed at providing new pharmacological tools, markers and mechanistic insights of the vesicular glutamate transporters (VGLUT). It was then extended to two other members of the same sub-family SLC17, sialin the sialic acid transporter which potentially transports Glu and Asp (Miyaji, 2008) and VNUT the nucleotide transporter characterized in 2008. (Sawada, 2008).

Vesicular Glutamate Transporter (VGLUT)
The VGLUTs have only been rather recently identified and characterized. Since the uptake assay is tricky the pharmacology of these transporters remains limited to a few compounds. Rose Bengal (RB IC50 20nM), Trypan Blue (TB IC50 50 nM), quinolines (IC50 40-200µM) and glutamate analogues (IC50 200µM- 5mM) make up the list of VGLUT inhibitors. We have initially synthesized Rose Bengal analogues then moved to Trypan Blue ones. Synthesis and pharmacological evaluation of dye analogues are still ongoing.
Sialic acid transporter (Sialin)
Several sialic acid analogues have been synthesized and tested. We chose the virtual high throughput screening (vHTS) approach to discover new inhibitors of sialin. A homology model was built, validated and docked with per-O-Ac 9-iodo-Neu5Ac a competitive inhibitor. A vHTS provided several hits among which, one was published (FR139317), others are being further evaluated.

Key words
: selective orthosteric ligands, transporter inhibitors, probe synthesis, structure-activity relationship, small molecule-protein interaction, structure function studies, docking, virtual high throughput screening, hit optimization.