Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives.
Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2), known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. laureestelle.cassagnes@gmail.com.
Laure-Estelle
LE
Cassagnes
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. nambine0508@yahoo.fr.
Nambinina
N
Rakotoarivelo
Synchrotron SOLEIL, L'Orme des Merisiers, BP 48 Saint-Aubin, 91190 Gif sur Yvette CEDEX, France. serena.sirigu@synchrotron-soleil.fr.
Serena
S
Sirigu
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. pierre.perio@univ-tlse3.fr.
Pierre
P
Pério
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. najahimco@yahoo.fr.
Ennaji
E
Najahi
Synchrotron SOLEIL, L'Orme des Merisiers, BP 48 Saint-Aubin, 91190 Gif sur Yvette CEDEX, France. leonard.chavas@synchrotron-soleil.fr.
Léonard M G
LM
Chavas
Synchrotron SOLEIL, L'Orme des Merisiers, BP 48 Saint-Aubin, 91190 Gif sur Yvette CEDEX, France. andrew.thompson@synchrotron-soleil.fr.
Andrew
A
Thompson
Vectalys S.A., Parc Technologique du Canal, Bâtiment Canal Biotech 2, 3, Rue des Satellites, 31400 Toulouse, France. regis.gayon@vectalys.com.
Régis
R
Gayon
Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy sur Seine, France. gilles.ferry@servier.com.
Gilles
G
Ferry
Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy sur Seine, France. jean.boutin@servier.fr.
Jean A
JA
Boutin
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. alexis.valentin@univ-tlse3.fr.
Alexis
A
Valentin
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. karine.reybier-vuattoux@univ-tlse3.fr.
Karine
K
Reybier
UMR 152 Pharma-Dev, Université de Toulouse, IRD, UPS, 31062 Toulouse, France. francoise.nepveu@univ-tlse3.fr.
Françoise
F
Nepveu
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011808:Quinone Reductases / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000962:Antimalarials; D005609:Free Radicals; D007211:Indoles; D017382:Reactive Oxygen Species; D011808:Quinone Reductases
human quinone reductase 2; indolones; inhibitor; malaria; mechanism