Approche pseudopeptidique du mécanisme d'action et d'inhibition de l'élastase leucocytaire humaine et du protéasome

Abstract : We have synthesized enzyme inhibitors to better understand their mechanism of recognition and inhibition, and further to dispose of new therapeutical agents. Our study of human leucocyte elastase (HLE) was about carbonylhydrazone [Psi][CO-NH-N=], ketomethylene [Psi][CO-CH2], ketomethyleneimino [Psi][CO-CH=N] and ketomethyleneamino [Psi][CO-CH2-NH] pseudopeptides. The carbonylhydrazone-peptides and the ketomethyleneimino-peptides are not recognized by the HLE because they are sterically constrained. The ketomethyleneamino are flexible and bind better to the catalytic site of the HLE. We began NMR studies of the inhibitor in the presence of elastase. It is necessary to dispose of flexible molecules to fit to the catalytic site of the HLE and study it better. Different original molecules have been synthesized for the proteasome. Inhibition profiles of some lipopeptides, synthesized from peptidic sequences that mimic degradation product of the proteasome, showed that the lipidic part interacts with one or several hydrophobic non catalytic sites, and that the peptidic part interacts with the catalytic site. We have designed and synthesized peptides including a photoactive group. By linkage to the proteasome after irradiation, it will be possible to locate the non catalytic site(s). At last, the first pseudopeptides targeting the proteasome have been prepared by introduction of a reduced moiety [Psi][CH2-NH] in a viral peptidic sequence. They present a specific inhibition of the chymotrypsic activity of the proteasome.
Document type :
Theses
File URL :
http://docnum.univ-lorraine.fr/prive/INPL_T_2003_BERNARD_E.pdf
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https://hal.univ-lorraine.fr/tel-01750105
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Submitted on : Thursday, March 29, 2018 - 12:37:59 PM
Last modification on : Tuesday, July 24, 2018 - 4:42:55 PM

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  • HAL Id : tel-01750105, version 1

Citation

Élise Bernard. Approche pseudopeptidique du mécanisme d'action et d'inhibition de l'élastase leucocytaire humaine et du protéasome. Alimentation et Nutrition. Institut National Polytechnique de Lorraine, 2003. Français. ⟨NNT : 2003INPL114N⟩. ⟨tel-01750105⟩

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