Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp.

Dominique Laurent (1, 2, 3, 4, 5) , Valérie Jullian (3) , Arnaud Parenty (6, 7) , Martine Knibiehler (8) , Dominique Dorin (9) , Sophie Schmitt (10) , Olivier Lozach , Nicolas Lebouvier (7) , Maryvonne Frostin (7) , Frédéric Alby (8) , Séverine Maurel , Christian Doerig (9) , Laurent Meijer (11) , Michel Sauvain (3)

1 INLN - Institut Non Linéaire de Nice Sophia-Antipolis
2 LPMC - Laboratoire de physique de la matière condensée
3 Pharmacochimie des substances naturelles et pharmacophores redox
4 Laboratoire des Substances Naturelles
5 Synapse Développement
6 ICSN - Institut de Chimie des Substances Naturelles
7 LIVE - Laboratoire Insulaire du Vivant et de l'Environnement
8 UMS 2646 Pierre Fabre-CNRS, Institut de Sciences et Technologies du Médicament de Toulouse, 3, rue des satellites, 31400 Toulouse, France
9 Controle de la Proliferation Cellulaire Chez Plasmodium Falciparum
10 REHSEIS (UMR_7596) - Recherches Epistémologiques et Historiques sur les Sciences Exactes et les Institutions Scientifiques
11 MCT - Molécules et cibles thérapeutiques

As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC(50) around 1 microM. Among a small panel of plasmodial protein kinases, xestoquinone showed modest protein kinase inhibitory activity toward PfPK5 and no activity toward PfPK7 and PfGSK-3. Xestoquinone showed in vitro antiplasmodial activity against a FCB1 P. falciparum strain with an IC(50) of 3 microM and a weak selectivity index (SI 7). Xestoquinone exhibited a weak in vivo activity at 5mg/kg in Plasmodium berghei NK65 infected mice and was toxic at higher doses.

Mots clés: Plasmodium; Xestoquinone; Antiplasmodial drug; Antimalarial drug; Plasmodium.

Domaines: Biochimie, Biologie Moléculaire; Chimie thérapeutique

Dominique Laurent, Valérie Jullian, Arnaud Parenty, Martine Knibiehler, Dominique Dorin, et al.. Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp.. Bioorganic and Medicinal Chemistry, 2006, 14 (13), pp.4477-4482. ⟨10.1016/j.bmc.2006.02.026⟩. ⟨hal-00169387⟩