A first step towards an original drug candidate against toxoplasmosis and malaria?

April 07 2009

The team coordinated by Mohamed-Ali Hakimi, working within the "Adaptation et pathogénie des micro-organismes" (Adaptation and pathogenesis of micro-organisms) Laboratory (CNRSUniversité Joseph Fourier Mixed Unit, Grenoble), in conjunction with researchers from Grenoble, Marseille and Paris, has just shown that a molecule - known as FR235222 - is capable of specifically repressing the activity of an enzyme produced by parasites of animal cells, such as those responsible for malaria and toxoplasmosis. It thus transpires that this molecule, which blocks the intracellular proliferation of the parasite, is a possible candidate in the quest for a new drug against these infections. The results of these works are published today in TheJournal of Experimental medicine

The life cycle of the Apicomplexa parasites, a family of animal cell parasites to which the Toxoplasma and Plasmodium parasites belong, alternates between intense proliferation and differentiation. It implicates a sophisticated control of the genes. However, the molecular mechanisms of this control remain obscure. Mohamed-Ali Hakimi, Inserm research leader, and his colleagues have put forward the hypothesis of a major contribution on the part of the structure of the chromosomes to the control of gene expression in Apicomplexa. For the purposes of validating this hypothesis, they tested the effect of several molecules capable of impairing structural modifications of histones [proteins which are linked to the DNA in order to form the chromatin (1)].

FR235222 is a ring-form peptide produced by a filamentous fungus. It was shown that FR23522 inhibits enzymes called histone deacetylases, themselves capable of increasing the level of condensation of certain regions of the chromatin and consequently of repressing the expression of certain genes. Thus, FR23522 would seem to allow certain genes that regulate the development of the parasite to express themselves by lifting the repression mediated by the histone deacetylases.

The work carried out by Mr Hakimi's team showed that the FR235222 peptide influences the expression of about 5% of the parasitic genes (369 out of an estimated total of 7817). The addition of this molecule in a culture of parasites induces the differentiation of the tachyzoites - replicative (proliferative) form - into bradyzoites - non-replicative form, FR235222 is thus capable of limiting or even inhibiting the proliferation of the parasite.

Lastly, the authors showed that the action of the FR235222 molecule on the parasites is facilitated by the unique presence of an amino acid inserted in the catalytic site of a histone deacetylase, exclusively in the Apicomplexa. "This enzyme is thus a serious candidate for the development of a drug against toxoplasmosis and malaria", in the opinion of the researchers. This work in the field of epigenetics (a discipline studying the factors modifying the expression of the genes) should in the medium term lead to the development of molecules equivalent to FR235222, forecast the authors. For Mr Hakimi and his colleagues, work in this field will also involve an improved study, in the animal (mouse), of the capacity of FR235222 to eliminate the parasites (Toxoplasma and Plasmodium).

Mr Hakimi benefits from an Inserm Interface Contract with Professor Pelloux of the University Hospital of Grenoble

(1) Form in which the genetic material is presented in the cell nuclei

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"Drug-inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites"

Alexandre Bougdour,1 Danièle Maubon,1,2 Patricia Baldacci,6 Philippe Ortet,3 Olivier Bastien,4 Anthony Bouillon,5 Jean-Christophe Barale,5 Hervé Pelloux,1,2 Robert Menard,6 Mohamed-Ali Hakimi,1*

1) UMR5163, Laboratoire Adaptation et Pathogénie des Micro-organismes, CNRS-Université Joseph Fourier Grenoble 1, BP 170, F-38042 Grenoble cedex 9, France.
2) Parasitologie-Mycologie, Département des Agents Infectieux, Centre Hospitalier Universitaire, BP 217, 38043 Grenoble, cedex 09, France.
3) CEA, DSV, IBEB, LEMiRE, CNRS, Université Aix-Marseille II, CEA Cadarache, F-13108 Saint-Paul-lezDurance, France
4) UMR 5168 CNRS-CEA-INRA-Université J. Fourier, Laboratoire de Physiologie Cellulaire Végétale; Département Réponse et Dynamique Cellulaire; CEA Grenoble, 17 rue des Martyrs, F-38054, Grenoble cedex
09, France.
5) Unité d'Immunologie Moléculaire des Parasites, Département de Parasitologie et de Mycologie, URA CNRS
2581, Institut Pasteur, Paris, 75724, France.
6) Unité de Biologie et Génétique du Paludisme, Institut Pasteur, Paris, France.

The Journal of experimental Medicine

Research contact

Mohamed-Ali Hakimi
Tel.: 04 76 63 74 69
Mel : Mohamed-ali.hakimi@ujf-grenoble.fr

Inserm press contact

Séverine Ciancia
Tel.: 01 44 23 60 86
Mel : presse@inserm.fr

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