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Abstract Paolo Minoprio
Trypanosoma cruzi proline racemases: potential targets for the development of a therapy against Chagas’infection and disease.

A. Berneman1, N. Chamond1, N. Coatnoan1, A. Cosson1, M. Alves-Ferreira1, M. Goytia1, D. Hermand1, Y. Janin2, P. Minoprio1.

1Unité d’Immunophysiopathologie Infectieuse, 2Unité de Chimie Organique, Institut Pasteur, Paris.

We identified a parasite B-cell mitogen, the first eukaryotic proline racemase (TcPRAC), essential to T. cruzi viability, virulence and fate. Saturation of TcPRAC catalytic site with specific inhibitors induces conformational changes of the protein precluding its interaction with B-cell ligands. Immunoprotection against parasite infection is possible by Œvaccination¹ of mice with TcPRAC sub-mitogenic doses or TcPRAC-DNA. A signature for PRACs predicted that putative PRACs are present in other pathogens. Ongoing experiments revealed that the solubility of the PRAC inhibitor can be improved by medical chemistry. Through structural and molecular dynamic analysis of PRAC with/without its inhibitors new insights were obtained on conformational opportunities for enzyme stabilization and ligand binding; yet, calculations of the protonation state of residues of the binding site were performed and appropriate pharmacophoric/docking models were derived for further virtual screening of compound libraries. Using PRAC-transgenic parasites, the presence of D-proline bound to parasite peptide chains was confirmed and current proteomic approaches are in progress to identify the respective proteins in soluble and membrane T. cruzi extracts.
Collaborations: A. Blondel, L. Masgrau, M. Nilges, Unité de Bio-informatique Structurale; C. Rougeot, Laboratoire de Recherche et Développement Pharmacologie des Régulations Neuro-endocrines; P. Alzari, Unité de Biochimie Structurale; M. Afshar, Ariana Pharma SA.

Key words: Chagas'disease, Proline racemase, Trypanosoma cruzi.

 
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