Recherche de nouvelles stratégies thérapeutiques ciblant les enzymes de biosynthèse des glycosaminoglycanes

Abstract : Glycosyltransferases (GTs) are an important family of enzymes involved in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans which are key components of cell plasma membranes and of the extracellular matrix, and are thus implicated in cell communication, adhesion, migration and proliferation. GTs are thus key players in numerous pathophysiological processes such as cancers, degenerative and genetic diseases. Among these GTs, ß1,4-galactosyltransférase 7 (ß4GalT7) is a potential therapeutic target since : i) it catalyzes a rate-limiting step in the early phase of the GAG chains biosynthesis, ii) it is implicated in a rare genetic connective tissue disorder (Ehlers-Danlos Syndrome), iii) its in vitro and in vivo activity can be modulated by exogenous xyloside molecules. This PhD work is focused on a structure/function study of the enzyme aiming to identify key amino acid residues that interact with 4-methylumbelliferyl-ß-D-xylose (4-MUX), taken as reference substrate. Y194, Y196 and Y199 have been identified as key residues for the architecture of the acceptor substrate binding site and establish interactions with 4-MUX. By contrast, H195, R226 and R270, a residue mutated in the progeroid form of Ehlers-Danlos Syndrome, should rather be considered as “modulating” residues towards the ß4GalT7 activity, H195 and R226 interacting with 4-MUX with their polypeptide backbone, and R270 via a flexible loop. This work guided the design of xylosidic compounds that would potentially inhibit the ß4GalT7 activity. Thus, a fluorinated derivative of 4-MUX appeared as an efficient in vitro and in cellulo inhibitor of the enzyme. Poorly cytotoxic, this compound also reduced the proliferation rate of cancer cells SW1353 and MB MDA 231. Altogether, these results offer new therapeutic strategies using xylosides as potential therapeutic agents in the treatment of cancer or rare genetic disorders
Document type :
Theses
Complete list of metadatas

https://hal.univ-lorraine.fr/tel-01754608
Contributor : Thèses Ul <>
Submitted on : Friday, March 30, 2018 - 9:54:51 AM
Last modification on : Sunday, April 1, 2018 - 1:17:00 AM

File

DDOC_T_2015_0182_SALIBA.pdf
Files produced by the author(s)

Identifiers

  • HAL Id : tel-01754608, version 1

Collections

Citation

Mineem Saliba. Recherche de nouvelles stratégies thérapeutiques ciblant les enzymes de biosynthèse des glycosaminoglycanes. Médecine humaine et pathologie. Université de Lorraine, 2015. Français. ⟨NNT : 2015LORR0182⟩. ⟨tel-01754608⟩

Share

Metrics

Record views

99

Files downloads

90