Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Chimie Bioorganique et Bioinorganique - LCBB

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Subject 1 (L. Salmon)
Synthesis and evaluation of enzyme inhibitors of therapeutic interest
R. Labruère, S. Pethe, F. Ramiandrasoa, L. Salmon

 

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

L. Salmon

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

  • PGI : Phosphoglucose isomerases
  • PMI : Phosphomannose isomerases
  • PRI : Phosphoriboses isomerases

Strategy:

  • Synthesis and kinetic evaluation of high-energy intermediate (HEI) or transition state (TS) analogue competitive inhibitors
  • Monosaccharidic and phosphorylated derivatives: hydroxamic acid, hydrazide, amide, amine...
  • Design of "phosphomimic" inhibitors


PGI-PMI catalyzed reactions and inhibitors

  • Overexpression of enzymes (C. albicans, H. sapiens...)
  • Cristallization of enzyme-substrat and enzyme-inhibitor complexes and X-ray structural studies (collaborations)
  • Theoretical studies through polarisable molecular modelling (SIBFA) of enzyme-inhibitor complexes (collaboration)

Results :

  • Syntheses of the most potent inhibitors ever obtained for these three enzymes
  • High resolution 3D structures of novel enzyme-inhibitor complexes
  • 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)