Institut de Chimie Moléculaire et des Matériaux d'Orsay

Chimie Bioorganique et Bioinorganique

1.3. Synthesis and evaluation of aldose-ketose isomerase inhibitors:
structural, mechanistic and therapeutic aspects

Objectives:

Study of the structural, mechanistic and therapeutic aspects of aldose-ketose isomerases :

PGI : Phosphoglucose isomérases
PMI : Phosphomannose isomérases
PRI : Phosphoriboses isomérases

Strategy:

Synthesis and kinetic evaluation of high energy intermediate (HEI) or transition state (TS) competitive inhibitors
Phosphorylated monosaccharide inhibitors of the type: hydroxamic acid, hydrazide, amide, amine ...
Design of "phosphomimic" inhibitors

Overexpression of enzymes (C. albicans, H. sapiens...)
Crystallization of enzyme-substrate and enzyme-inhibitor complexes and structural studies by X-ray diffraction (collaborations)
Theoretical studies using polarizable molecular modeling (SIBFA) of enzyme-inhibitor complexes (collaboration)

Results:

Synthèses des inhibiteurs les plus puissants jamais obtenus pour ces trois enzymes
Syntheses of the most potent inhibitors ever obtained for these three enzyme
- 3D Structure (RX) : PDB 1KOJ - RmPGI/5PAH
- 3D Structure (SIBFA) : CaPMI-5PAH
Determination of detailed isomerization mechanisms

Collaborations :

Dr. N. Gresh, Lab. Chimie Théorique, Univ. Pierre et Marie Curie, Paris (France)
Prof. C. J. Jeffery, Univ. of Illinois at Chicago, Chicago (USA)
Prof. H. van Tilbeurgh & Dr. I. Gallay, I2BC, Univ. Paris-Sud/Univ. Paris-Saclay, Orsay (France)
Prof. S. L. Mowbray, Uppsala Univ., Uppsala (Suède)