Design et synthèse de plates-formes polyfonctionnelles pour l'inhibition de protéases

Beck, Joséphine
(2007)

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Authors
  • Beck, Joséphine
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Supervisors
Marchand, Jacqueline
Abstract
(en) The production of b-lactamases represents the most widespread and often the most efficient mechanism devised by bacteria to escape to the lethal action of b-lactam antibiotics. Our research focuses on the synthesis and the biological evaluation of potential inhibitors of classes A, B, C and D b-lactamases. The crystallization of class A b-lactamase BS3 from a citric acid buffer revealed the unexpected role of this compound which is perfectly located in the enzymic cavity. The citrate is an inhibitor of all class A b-lactamases at the micromolar level. These recent observations carried out in the Centre d?Ingénierie des Protéines (université de Liège) led us to consider the citrate as a lead for the design of new selective and high affinity inhibitors of b-lactamases. We tried to increase the binding in the enzymic cavity by replacing the alcohol function by an amine function on which we could fix a variety of lateral chains. We have also considered the replacement of one (or two) carboxylic functions with the bioisoster phosphonic acids and the lengthening of one or two acidic chains to create novel interactions. Several derivatives of the amino-bioisoster of citric acid have been synthesized with carboxylic or ester functions and the biological activity of aminocitrate derivatives has been evaluated against PBPs (Penicillin Binding Proteins). The complex between the aminocitrate and BS3 has been analysed by X-Ray diffraction. The amino phosphonic and bis-phosphonic derivatives have been synthesized and the biological evaluation has been achieved against PBPs. Finally, the complexing capacity of several molecules has been evaluated by mass spectrometry.
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Beck, J. (2007). Design et synthèse de plates-formes polyfonctionnelles pour l’inhibition de protéases. https://hdl.handle.net/2078.5/129263